Ready ... Go: Amplitude of the fMRI Signal Encodes Expectation of Cue Arrival Time

What happens when the brain awaits a signal of uncertain arrival time, as when a sprinter waits for the starting pistol? And what happens just after the starting pistol fires? Using functional magnetic resonance imaging (fMRI), we have discovered a novel correlate of temporal expectations in several brain regions, most prominently in the supplementary motor area (SMA). Contrary to expectations, we found little fMRI activity during the waiting period; however, a large signal appears after the “go” signal, the amplitude of which reflects learned expectations about the distribution of possible waiting times. Specifically, the amplitude of the fMRI signal appears to encode a cumulative conditional probability, also known as the cumulative hazard function. The fMRI signal loses its dependence on waiting time in a “countdown” condition in which the arrival time of the go cue is known in advance, suggesting that the signal encodes temporal probabilities rather than simply elapsed time. The dependence of the signal on temporal expectation is present in “no-go” conditions, demonstrating that the effect is not a consequence of motor output. Finally, the encoding is not dependent on modality, operating in the same manner with auditory or visual signals. This finding extends our understanding of the relationship between temporal expectancy and measurable neural signals

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

Understanding the low take-up of home-based dialysis through a shared decision-making lens:a qualitative study

Objectives To explore how people with chronic kidney disease who are pre-dialysis, family members and healthcare professionals together navigate common shared decision-making processes and to assess how this impacts future treatment choice.Design Coproductive qualitative study, underpinned by the Making Good Decisions in Collaboration shared decision-model. Semistructured interviews with a purposive sample from February 2019 - January 2020. Interview data were analysed using framework analysis. Coproduction of logic models/roadmaps and recommendations.Setting Five Welsh kidney services.Participants 95 participants (37 patients, 19 family members and 39 professionals); 44 people supported coproduction (18 patients, 8 family members and 18 professionals).Findings Shared decision-making was too generic and clinically focused and had little impact on people getting onto home dialysis. Preferences of where, when and how to implement shared decision-making varied widely. Apathy experienced by patients, caused by lack of symptoms, denial, social circumstances and health systems issues made future treatment discussions difficult. Families had unmet and unrecognised needs, which significantly influenced patient decisions. Protocols containing treatment hierarchies and standards were understood by professionals but not translated for patients and families. Variation in dialysis treatment was discussed to match individual lifestyles. Patients and professionals were, however, defaulting to the perceived simplest option. It was easy for patients to opt for hospital-based treatments by listing important but easily modifiable factors.Conclusions Shared decision-making processes need to be individually tailored with more attention on patients who could choose a home therapy but select a different option. There are critical points in the decision-making process where changes could benefit patients. Patients need to be better educated and their preconceived ideas and misconceptions gently challenged. Healthcare professionals need to update their knowledge in order to provide the best advice and guidance. There needs to be more awareness of the costs and benefits of the various treatment options when making decisions

Relationship between abundance of juvenile rockfishes (Sebastes spp.) and environmental variables documented off northern California and potential mechanisms for the covariation

We estimated annual abundance of juvenile blue (Sebastes mystinus), yellowtail (S. f lavidus), and black (S. melanops) rockfish off northern California over 21 years and evaluated the relationship of abundance to oceanographic variables (sea level anomaly, nearshore temperature, and offshore Ekman transport). Although mean annual abundance was highly variable (0.01−181 fish/minute), trends were similar for the three species. Sea level anomaly and nearshore temperature had the strongest relationship with interannual variation in rockfish abundance, and offshore Ekman transport did not correlate with abundance. Oceanographic events occurring in February and March (i.e., during the larval stage) had the strongest relationship with juvenile abundance, which indicates that year-class strength is determined during the larval stage. Also of note, the annual abundance of juvenile yellowtail rockfish was positively correlated with year-class strength of adult yellowtail rockfish; this finding would indicate the importance of studying juvenile abundance surveys for management purposes

Replication of Acute Kidney Injury e-Alerts

Background Acute Kidney Injury (AKI) is a serious condition occurring in approximately 20% of emergency hospital admissions. A Welsh AKI e-Alert (electronic alerts) system was introduced from 2013 with the aim of improving patient outcomes through early recognition of AKI. Objectives Our objective is to replicate the AKI e-Alert system which has been implemented throughout Wales and create a retrospective AKI cohort to facilitate data linkage. Methods The e-alert algorithm was re-produced in SQL (Structured Query Language) and applied to serum creatinine (SCr) values 2011-2014 held in the Secure Anonymised Information Linkage (SAIL) Databank. The algorithm utilises ratios between current SCr value (C1) to lowest SCr value within the previous 7 days (RV1), SCr median values from the previous 8-365 days (RV2), and lowest SCr within 48hrs (D). >50% increase in RV1 or RV2 or >26µmol/L above D triggers an alert. We created a temporal AKI cohort by using a renal dataset to exclude patients undergoing chronic dialysis. Findings 2,407,590 SCr tests were performed on adult patients with 2,077,493 of these coming from people in Abertawe Bro Morgannwg University Health Board who were not on dialysis at the time of the test. The average population for 2011-2014 was 520,293. 85,272 (4.1%) of these tests triggered alerts for AKI. The average incidence of AKI per 100,000 population per year for 2011-2014 was 1,717. The average first AKI episodes per year for 2011-2014 respectively were stage 1 (least severe): 79.2%; stage 2: 13.5%; stage 3 (most severe): 7.3%. Conclusions The e-alert can be effectively reproduced using SQL to identify AKI in this large dataset, enabling subsequent validation of these alerts and evaluation of their impact through multisource data linkage

Which factors determine treatment choices in patients with advanced kidney failure? a protocol for a co-productive, mixed methods study

Introduction Kidney disease is common, affecting up to 1 in 10 of the adult population, and the numbers are expected to rise over the next decade. There are three main treatments that are available to patients with kidney disease: transplantation, dialysis and supportive care without dialysis. Dialysis can occur in a dialysis unit or in a person’s home, but unit-based dialysis remains the most common initial treatment for patients in Wales. This is a cause for concern as most studies suggest that it is associated with the lowest quality of life and the highest mortality, and is a more expensive treatment option.This study aims to identify the factors that lead to patients choosing unit-based haemodialysis rather than home-based dialysis with a view to informing future changes in patient education and service commissioning in Wales. A secondary aim is to determine if the co-production of research leads to more sustainable services.Methods and analysis This mixed-method study taking place between October 2018 and September 2020 will use a sequential explanatory design whereby the descriptive quantitative cross-sectional analysis of linked health and administrative data sets inform qualitative data collection from patients, carers and health and care professionals. Qualitative findings will be used to interpret or explain quantitative descriptive results. Additional strands to the study include a review of materials and education provided to patients and an economic review of treatment modalities.Ethics and dissemination The study will be conducted in accordance with the principles expressed in the Declaration of Helsinki. It has full approval from Health and Care Research Wales Research Ethics Committee #5. As a co-productive study involving patients, clinicians, third sector partners and academics, findings from this study will be shared on a continual basis. Study results will be published in peer-reviewed journals and presented at national and international conferences

Validation of Acute Kidney Injury e-alert system in Wales

Introduction Acute Kidney Injury (AKI) is a serious condition associated with increased mortality/morbidity and occurs in approximately 20% of hospital admissions. A Welsh AKI alert (e-alert) system has been in place since 2014, aiming to improve patient outcomes and care standards through early recognition of AKI using a retrospective dataset. Objectives and Approach The e-alert algorithm was re-produced in SQL (structured query language) and applied to serum creatinine (SCr) values for patients from pathology departments in Abertawe Bro Morgannwg health board (ABMUHB)  2011-2014, held in the Secure Anonymised Information Linkage (SAIL) databank. The algorithm utilises ratios between current SCr value (C1) to lowest SCr value within the previous 7 days (RV1), SCr median values from the previous 8-365 days (RV2), and lowest SCr within 48hrs (D). >50% increase in RV1 or RV2 or >26µmol/L above D triggers an alert. Using a renal dataset to create a timeline we created a temporal AKI cohort. Results 2,407,590 SCr tests were performed on adult patients with 2,077,493 of these coming from people in the local area who were not on renal replacement during the time-period. The average ABMUHB population for 2011-2014 was 520,293 (2011: 517,981; 2012: 519,481; 2013: 520,710; 2014: 523,001). 85,272 (4.1%) of these tests triggered alerts for AKI. The incidence per 100,000 population of AKI for 2011-2014 were 1767, 1723, 1717, 1660 (average 1,717). The first AKI episodes per year for 2011-2014 respectively were stage 1 (least severe): 78.9%, 79.3%, 79.3%, 79.4% (average 79.2%); stage 2: 13.3%, 13.7%, 13.1%, 13.7% (average 13.5%);  stage 3 (most severe): 7.8%, 7.0%, 7.6%, 6.9% (average 7.3%). Conclusion/Implications The AKI e-alert algorithm can be effectively reproduced using standard query language. The AKI findings in this population are comparable to others published. The use of a renal dataset using both records of renal replacement timeline and individual dialysis session may identify and rectify where alerts have not been generated

Defining Acute Kidney Injury Episodes

Background Acute Kidney Injury (AKI) is a common, serious condition effecting up to 20% of all hospital admissions in the UK. AKI has an agreed definition for its recognition, however there is no consensus for the duration of an AKI episode. Main Aim To describe four different potential definitions of an AKI episode. Method We identified AKI using an SQL (Structured Query Language) based algorithm (an implementation of the NHS England eAlert algorithm) applied to serum creatinine (SCr) results from a South Wales population of ~518,000 people, held in the Secure Anonymised Information Linkage (SAIL) Databank. Using a person’s index AKI case, we applied four different rules to define an episode of AKI. These definitions are: ALERTS - until they no longer trigger an AKI eAlert, 90 DAYS - until 90 days post first AKI test and <1.2/<1.5 until the SCr recovers to <1.2 or 1.5 times their baseline creatinine. Results There were 1,832,122 SCr tests in 340,908 people between 2011-2013, of which 93,843 were alerts (5.12%). This fell to 81,948 alerts in 21,979 patients when dialysis and transplant patients were excluded. Of these patients with AKI 7,792 (35.5%) were dead at 1 year after their first episode. There were 31,505, 33,759, 26,657, 34,904 episodes in patients by <1.2, <1.5, 90 Days and ALERTS definitions respectively. Conclusion AKI episodes can be created in SAIL using SQL, and by adjusting the definition we see a variation in the number of episodes that a patient experiences. Once described, this cohort can be used to define a gold standard for AKI in future analysis

Assessing the efficacy of coproduction to better understand the barriers to achieving sustainability in NHS chronic kidney services and create alternate pathways

CONTEXT: Too many people living with chronic kidney disease are opting for and starting on hospital‐based dialysis compared to a home‐based kidney replacement therapy. Dialysis services are becoming financially unsustainable. OBJECTIVE: This study aimed to assess the efficacy of coproductive research in chronic kidney disease service improvement to achieve greater sustainability. DESIGN: A 2‐year coproductive service improvement study was conducted with multiple stakeholders with the specific intention of maximizing engagement with the national health kidney services, patients and public. SETTING AND PARTICIPANTS: A national health kidney service (3 health boards, 18 dialysis units), patients and families (n = 50), multidisciplinary teams including doctors, nurses, psychologists, social workers, and so forth (n = 68), kidney charities, independent dialysis service providers and wider social services were part of this study. FINDINGS: Coproductive research identified underutilized resources (e.g., patients on home dialysis and social services) and their potential, highlighted unmet social care needs for patients and families and informed service redesign. Education packages were reimagined to support the home dialysis agenda including opportunities for wider service input. The impacts of one size fits all approaches to dialysis on specialist workforce skills were made clearer and also professional, patient and public perceptions of key sustainability policies. DISCUSSION AND CONCLUSIONS: Patient and key stakeholders mapped out new ways to link services to create more sustainable models of kidney health and social care. Maintaining principles of knowledge coproduction could help achieve financial sustainability and move towards more prudent adult chronic kidney disease services. PATIENT OR PUBLIC CONTRIBUTION: Involved in developing research questions, study design, management and conduct, interpretation of evidence and dissemination