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The formation of mesoporous gold sponges by explosive decomposition of 'knallgold' (also known as 'fulminating' gold) is studied. Proof-of-principle experiments are conducted and then the phenomena are further investigated using 'toy physics' molecular dynamics simulations. The simulations invoked various ratios of a volatile Lennard-Jones element G and a noble metal element N. In both experiment and simulation the morphology of the resulting sponge is found to depend on the stoichiometry of the starting material. As the mole fraction of G (χ G ) is increased from 0.5 to close to 1.0 in the simulations, the morphology of the sponges changes from closed to open, with a corresponding increase in the average mean curvature from 0 to +0.12 inverse Lennard-Jones length (L) units. The average Gaussian curvature of the simulated sponges is always negative, with the minimum value of 0.05 L -2 being found for χ G ≈0.65. In broad agreement with experiment, sponge formation in the simulations is bounded by stoichiometry; no sponges form if χ G is <0.52, for χ G between 0.52 and 0.70 the sponge is characterized by vermicular cavities whereas classic bicontinuous fibrous sponges form for 0.70<χ G <0.85 and, finally, discrete particles result if χ G >0.85., (© 2024 Wiley-VCH GmbH.)

Objective: To quantify the potential advantages of using 10 year risk prediction models for cardiovascular disease, in combination with risk thresholds specific to both age and sex, to identify individuals at high risk of cardiovascular disease for allocation of statin treatment., Design: Prospective open cohort study., Setting: Primary care data from the UK Clinical Practice Research Datalink GOLD, linked with hospital admissions from Hospital Episode Statistics and national mortality records from the Office for National Statistics in England, 1 January 2006 to 31 May 2019., Participants: 1 046 736 individuals (aged 40-85 years) with no cardiovascular disease, diabetes, or a history of statin treatment at baseline using data from electronic health records., Main Outcome Measures: 10 year risk of cardiovascular disease, calculated with version 2 of the QRISK cardiovascular disease risk algorithm (QRISK2), with two main strategies to identify individuals at high risk: in strategy A, estimated risk was a fixed cut-off value of ≥10% (ie, as per the UK National Institute for Health and Care Excellence guidelines); in strategy B, estimated risk was ≥10% or ≥90th centile of age and sex specific risk distributions., Results: Compared with strategy A, strategy B stratified 20 241 (149.8%) more women aged ≤53 years and 9832 (150.2%) more men aged ≤47 years as having a high risk of cardiovascular disease; for all other ages the strategies were the same. Assuming that treatment with statins would be initiated in those identified as high risk, differences in the estimated gain in cardiovascular disease-free life years from statin treatment for strategy B versus strategy A were 0.14 and 0.16 years for women and men aged 40 years, respectively; among individuals aged 40-49 years, the numbers needed to treat to prevent one cardiovascular disease event for strategy B versus strategy A were 39 versus 21 in women and 19 versus 15 in men, respectively., Conclusions: This study quantified the potential gains in cardiovascular disease-free life years when implementing prevention strategies based on age and sex specific risk thresholds instead of a fixed risk threshold for allocation of statin treatment. Such gains should be weighed against the costs of treating more younger people with statins for longer., Competing Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from British Heart Foundation (BHF), BHF Cambridge Centre for Research Excellence, National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, Chinese Scholarship Council, NIHR Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics, NIHR BTRU in Donor Health and Behaviour, and Innovative Medicines Initiative-2 Joint Undertaking for the submitted work; MA is an employee of AstraZeneca; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: This analysis examined the baseline characteristics and clinical outcomes of patients with chronic kidney disease (CKD) and rapid or non-rapid estimated glomerular filtration rate (eGFR) decline, using retrospective data from DISCOVER CKD (ClinicalTrials.gov, NCT04034992)., Methods: Data (2008-2020) were extracted from UK Clinical Practice Research Datalink, US TriNetX, US Limited Claims and Electronic Health Record Dataset, and Japan Medical Data Vision. Patients with CKD (two consecutive eGFR measures < 75 mL/min/1.73 m 2 recorded 90-730 days apart) were included. Rapid eGFR decline was defined as an annual decline of > 4 mL/min/1.73 m 2 at 2 years post-index; non-rapid eGFR decline was defined as an annual decline of ≤ 4 mL/min/1.73 m 2 . Clinical outcomes assessed included all-cause mortality, kidney outcomes (composite risk of kidney failure [progression to CKD stage 5] or > 50% eGFR decline, and kidney failure alone), cardiovascular events-including major adverse cardiovascular events (MACE; non-fatal myocardial infarction/stroke and cardiovascular death)-and all-cause hospitalization., Results: Across databases, rapid eGFR decline occurred in 13.7% of 804,237 eligible patients. Mean annual eGFR decline ranged between - 6.21 and - 6.86 mL/min/1.73 m 2 in patients with rapid eGFR decline versus between - 0.11 and - 0.77 mL/min/1.73 m 2 in patients with non-rapid eGFR decline. Rapid eGFR decline was associated with increased comorbidity burden and medication prescriptions. Across databases, the composite risk of kidney failure or > 50% decline in eGFR was significantly greater in patients with rapid versus non-rapid eGFR decline (P < 0.01); all-cause mortality, kidney failure alone, MACE, and all-cause hospitalization each significantly increased in two databases (P < 0.01-0.05)., Conclusion: Understanding patient factors associated with rapid eGFR decline in patients with CKD may help identify individuals who would benefit from proactive management to minimize the risk of adverse outcomes., Trial Registration: ClinicalTrials.gov identifier, NCT04034992., (© 2024. The Author(s).)

Background: Clinical practice guidelines for patients with chronic kidney disease (CKD) recommend regular monitoring and management of kidney function and CKD risk factors. However, the majority of patients with stage 3 CKD lack a diagnosis code, and data on the implementation of these recommendations in the real world are limited., Aim: To assess the implementation of guideline-directed monitoring and management practices in the real world in patients with stage 3 CKD without a recorded diagnosis code., Methods: REVEAL-CKD (NCT04847531) is a multinational, observational study of patients with stage 3 CKD. Eligible patients had ≥2 consecutive estimated glomerular filtration rate (eGFR) measurements indicative of stage 3 CKD recorded >90 and ≤730 days apart, lacked an International Classification of Diseases 9/10 diagnosis code corresponding to CKD any time before and up to 6 months after the second eGFR measurement. Testing of key measures of care quality were assessed., Results: The study included 435,971 patients from 9 countries. In all countries, the prevalence of urinary albumin-creatinine ratio and albuminuria testing was low. Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker and statin prescriptions were highly variable, and sodium-glucose cotransporter-2 inhibitor prescriptions remained below 21%. Blood pressure measurements were recorded in 20.2%-89.9% of patients., Conclusions: Overall, a large proportion of patients with evidence of stage 3 CKD did not receive recommended, guideline-directed monitoring and management. The variability in standard of care among countries demonstrates a clear opportunity to improve monitoring and management of these patients, most likely improving long-term outcomes., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Hyperkalaemia is a barrier to achieving optimal, guideline-directed treatment with renin-angiotensin-aldosterone system inhibitors (RAASis) in patients with chronic kidney disease (CKD) and/or heart failure (HF). This study describes the association between hyperkalaemia-related RAASi treatment reduction and the number of hospitalized days in patients with CKD and/or HF in Sweden and Japan., Methods: Using data from health registers and hospital medical records, patients with CKD and/or HF currently receiving RAASis who experienced an index hyperkalaemia episode were identified and categorized as having maintained or reduced RAASi treatment post-index; propensity score matching (1:1) was applied to balance the groups in terms of baseline characteristics. Changes in the number of all-cause, CKD- and HF-related hospitalized days per patient-year during 6 months pre- versus post-index and the number of days alive and out of hospital (DAOH) during 6 months post-index were described., Results: Overall, 20 824 and 7789 patients were included from Sweden and Japan, respectively, 42% and 38% of whom reduced their RAASi treatment after the index hyperkalaemia episode. During the 6 months post-index, all-cause hospitalization increased by 18.2 days [95% confidence interval (CI) 17.0-19.2] per person-year in Sweden and 17.9 days (95% CI 17.4-18.5) per person-year in Japan among patients with reduced RAASi treatment compared with increases of 9.4 days (95% CI 8.6-10.4) and 8.5 days (95% CI 8.0-9.0) per person-year, respectively, among patients with maintained RAASi treatment. The mean DAOH was 121.5 [standard deviation (SD) 75.0] in Sweden and 141.7 (SD 54.5) in Japan among patients with reduced RAASi treatment compared with 154.0 (SD 51.3) and 157.5 (SD 31.6), respectively, among patients with maintained RAASi treatment., Conclusion: Patients whose RAASi treatment was reduced after a hyperkalaemia episode had more hospitalized days and fewer DAOH compared with patients whose RAASi treatment was maintained., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD + can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD + precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD + metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD + boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.

Crossword puzzles have been utilised as a means of health professions education (HPE) gamification. A systematic review conducted in accordance with PRISMA guidelines was performed to evaluate the educational impact and describe the characteristics of crosswords in HPE contexts. Twenty-nine studies fulfilled inclusion criteria. Crossword puzzles are an enjoyable learning activity and provide positive educational impact. The available evidence suggests crossword puzzles increase student knowledge on objective measures., Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-024-02085-x., Competing Interests: Conflict of InterestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Author(s) 2024.)

Background: This observational cohort study compared the likelihood of maintained (stabilized/up-titrated) renin-angiotensin-aldosterone system inhibitor (RAASi) therapy at 6 months following hyperkalaemia in patients with chronic kidney disease (CKD) and/or heart failure (HF) from the USA, Japan and Spain who received sodium zirconium cyclosilicate (SZC) for at least 120 days, relative to those with no prescription for a potassium (K + ) binder., Methods: Using health registers and hospital medical records, patients with CKD and/or HF receiving RAASi therapy who experienced a hyperkalaemia episode were identified. Propensity score (PS) matching (1:4) was applied to balance the SZC cohort to the no K + binder cohort on baseline characteristics. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6 months in the SZC versus no K + binder cohorts., Results: The PS-matched SZC cohort included 565 (USA), 776 (Japan) and 56 (Spain) patients; the no K + binder cohort included 2068, 2629 and 203 patients, respectively. At 6 months, 68.9% (USA), 79.9% (Japan) and 69.6% (Spain) in the SZC cohorts versus 53.1% (USA), 56.0% (Japan) and 48.3% (Spain) in the no K + binder cohorts had maintained RAASi therapy. Meta-analysed across countries, the odds ratio of maintained RAASi therapy in the SZC cohort versus no K + binder cohort was 2.56 (95% confidence interval 1.92-3.41; P  < .0001)., Conclusions: In routine clinical practice across three countries, patients treated with SZC were substantially more likely to maintain guideline-concordant RAASi therapy at 6 months following hyperkalaemia relative to patients with no K + binder treatment., Competing Interests: A.R. has received research grants and consulting fees from AstraZeneca. C.V.P. Jr has received consultancy fees from AstraZeneca. I.J.S.L. is an employee of Hospital Universitari i Politècnic La Fe and has served on the speakers bureaus of AstraZeneca and Novartis. E.L. is an employee and stockholder of AstraZeneca. M.A. is an employee of AstraZeneca. S.F. is an employee and stockholder of AstraZeneca. A.A. is an employee and stockholder of AstraZeneca. I.H. is an employee of Atrys Health, a service company for AstraZeneca. T.M. has received honoraria for lectures from AstraZeneca. E.K. reports no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Epigenetic 'clocks' based on DNA methylation have emerged as the most robust and widely used aging biomarkers, but conventional methods for applying them are expensive and laborious. Here we develop tagmentation-based indexing for methylation sequencing (TIME-seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-seq, we applied multi-tissue and tissue-specific epigenetic clocks in over 1,800 mouse DNA samples from eight tissue and cell types. We show that TIME-seq clocks are accurate and robust, enriched for polycomb repressive complex 2-regulated loci, and benchmark favorably against conventional methods despite being up to 100-fold less expensive. Using dietary treatments and gene therapy, we find that TIME-seq clocks reflect diverse interventions in multiple tissues. Finally, we develop an economical human blood clock (R > 0.96, median error = 3.39 years) in 1,056 demographically representative individuals. These methods will enable more efficient epigenetic clock measurement in larger-scale human and animal studies., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The impact of vaccination prior to infection on postacute sequelae of coronavirus disease 2019 (COVID-19, PASC), also known as long COVID, remains unclear. Here we assess the protective effect of vaccination on long COVID in a community-based setting., Methods: The Immunity Associated with SARS-CoV-2 (IASO) study is an ongoing prospective cohort of working adults that began in October 2020. Participants are actively followed for severe acute respiratory syndrome coronavirus 2 infection. We compared the prevalence of symptoms and symptom severity in vaccinated compared to unvaccinated cases. Our primary definition of long COVID was the presence of symptoms at 90 days postinfection; 30 days postinfection was also examined., Results: Overall, by 90 days postinfection, 13% of cases had long COVID, with 27% of unvaccinated cases and 8% of vaccinated cases reporting long COVID (relative risk [RR], 0.31 [95% confidence interval {CI}, .22-.42]). Vaccination was also associated with significantly lower average severity scores at all timepoints (eg, relative severity at 90 days postinfection: -2.70 [95% CI, -1.68 to -3.73]). In the pre-Omicron era, 28% of unvaccinated cases and 18% of vaccinated cases reported long COVID ( P = .07), and vaccinated cases reported less severe symptoms including less difficulty breathing ( P = .01; 90-day RR, 0.07)., Conclusions: Vaccinated cases had lower prevalence of long COVID and reduced symptom severity., Competing Interests: Potential conflicts of interest. A.G. has served on a respiratory syncytial virus vaccine scientific advisory board for Janssen Pharmaceuticals and on a COVID-19 scientific advisory board for Gilead Sciences. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Prefrontal synthesis (PFS) is a component of constructive imagination. It is defined as the process of mentally juxtaposing objects into novel combinations. For example, to comprehend the instruction "put the cat under the dog and above the monkey," it is necessary to use PFS in order to correctly determine the spatial arrangement of the cat, dog, and monkey with relation to one another. The acquisition of PFS hinges on the use of combinatorial language during early childhood development. Accordingly, children with developmental delays exhibit a deficit in PFS, and frequent assessments are recommended for such individuals. In 2018, we developed the Mental Synthesis Evaluation Checklist (MSEC), a parent-reported evaluation designed to assess PFS and combinatorial language comprehension. In this manuscript we use MSEC to identify differences in combinatorial language acquisition between ASD (N = 29,138) and neurotypical (N = 111) children. Results emphasize the utility of the MSEC in distinguishing language deficits in ASD from typical development as early as 2 years of age (p < 0.0001)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Clinical leadership is necessary to improve the performance of large public hospitals. Trainee medical officers (TMOs) are important stakeholders in organisation-wide initiatives that affect the medical workforce and support clinician engagement. This case study describes the development of a representative body known as the 'TMO Forum' within the Central Adelaide Local Health Network as a mechanism to promote engagement between medical trainees and the hospital executive to facilitate escalation and discussion of system-based issues. Over the past 8 years, this group has evolved into a community of practice with steady and sustained growth since inception. Trainees have fostered relationships with the executive, and have engaged in leadership and quality improvement initiatives. Here we explore the evolution, value and barriers to success of the TMO Forum. Our discussion is supplemented with findings from anonymous online evaluation surveys of both the TMO and executive stakeholder groups. We propose that initiatives such as the described may offer reciprocal benefits to both constituent groups regarding communication, and that the development of a dedicated community of practice will enhance engagement of TMOs in health service improvement initiatives and advocacy. However, there are obstacles to overcome in order to attract a greater number of trainees and maximise the benefits from this initiative.

The biological brain is a highly efficient computational system in which information processing is performed via electrical spikes. Neuromorphic computing systems that work on similar principles could support the development of the next generation of artificial intelligence and, in particular, enable low-power edge computing. Percolating networks of nanoparticles (PNNs) have previously been shown to exhibit critical spiking behavior, with promise for highly efficient natural computation. Here we employ a rate coding scheme to show that PNNs can perform Boolean operations and image classification. Near perfect accuracy is achieved in both tasks by manipulating the spiking activity using certain control voltages. We demonstrate that the key to successful computation is that nanoscale tunnel gaps within the percolating networks transform input data through a powerful modulus-like nonlinearity. These results provide a basis for implementation of further computational schemes that exploit the brain-like criticality of these networks.

Introduction: Ankle instability in children due to soft tissue injury usually resolves after non-operative treatment. However, some children and adolescents with chronic instability require surgical treatment. A rarer cause of developing ankle instability is injury to the ligament complex in the presence of os subfibulare, an accessory bone inferior to the lateral malleolus. The aim of this study was to assess the results of operative management of chronic ankle instability in children with os subfibulare., Materials and Methods: 16 children with os subfibulare and chronic ankle instability who failed non-operative treatment were enrolled prospectively into the study. One child was lost to follow-up and excluded from analysis. The mean age at the time of the surgery was 14 years and 2 months (range 9.5-17 years). The mean follow-up time was 43.2 months (range 28-48 months). Surgical treatment in all cases involved removal of os subfibulare and a modified Broström-Gould lateral complex reconstruction with anchors. Ankle status was assessed before and after surgery with The 100 mm Visual Analogue Scale and Foot and Ankle Outcome Score questionnaire., Results: The mean Foot and Ankle Outcome Score improved from 66.8 to 92.3 (p < 0.001). Pain level improved from 67.1 preoperatively to 12.7 (p < 0.001). All children reported improvement in their ankle stability. There was one case of scar hypersensitivity that improved during observation and one superficial wound infection that resolved with oral antibiotics. One child reported intermittent pain without symptoms of instability following another injury., Conclusions: Ankle joint sprain with associated injury to os subfibulare complex can lead to chronic instability in children. If conservative management fails, then surgical treatment with modified Broström-Gould technique and excision of accessory bone is a safe and reliable method., (© 2023. The Author(s).)

Objective: To provide quantitative evidence for systematically prioritising individuals for full formal cardiovascular disease (CVD) risk assessment using primary care records with a novel tool (eHEART) with age- and sex- specific risk thresholds., Methods and Analysis: eHEART was derived using landmark Cox models for incident CVD with repeated measures of conventional CVD risk predictors in 1,642,498 individuals from the Clinical Practice Research Datalink. Using 119,137 individuals from UK Biobank, we modelled the implications of initiating guideline-recommended statin therapy using eHEART with age- and sex-specific prioritisation thresholds corresponding to 5% false negative rates to prioritise adults aged 40-69 years in a population in England for invitation to a formal CVD risk assessment., Results: Formal CVD risk assessment on all adults would identify 76% and 49% of future CVD events amongst men and women respectively, and 93 (95% CI: 90, 95) men and 279 (95% CI: 259, 297) women would need to be screened (NNS) to prevent one CVD event. In contrast, if eHEART was first used to prioritise individuals for formal CVD risk assessment, we would identify 73% and 47% of future events amongst men and women respectively, and a NNS of 75 (95% CI: 72, 77) men and 162 (95% CI: 150, 172) women. Replacing the age- and sex-specific prioritisation thresholds with a 10% threshold identify around 10% less events., Conclusions: The use of prioritisation tools with age- and sex-specific thresholds could lead to more efficient CVD assessment programmes with only small reductions in effectiveness at preventing new CVD events., Competing Interests: During the drafting of the manuscript, M.A. became an employee of AstraZeneca. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Chung 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 The aim of this study was to provide quantitative evidence of the use of polygenic risk scores for systematically identifying individuals for invitation for full formal cardiovascular disease (CVD) risk assessment. Methods and Results A total of 108 685 participants aged 40 to 69 years, with measured biomarkers, linked primary care records, and genetic data in UK Biobank were used for model derivation and population health modeling. Prioritization tools using age, polygenic risk scores for coronary artery disease and stroke, and conventional risk factors for CVD available within longitudinal primary care records were derived using sex-specific Cox models. We modeled the implications of initiating guideline-recommended statin therapy after prioritizing individuals for invitation to a formal CVD risk assessment. If primary care records were used to prioritize individuals for formal risk assessment using age- and sex-specific thresholds corresponding to 5% false-negative rates, then the numbers of men and women needed to be screened to prevent 1 CVD event are 149 and 280, respectively. In contrast, adding polygenic risk scores to both prioritization and formal assessments, and selecting thresholds to capture the same number of events, resulted in a number needed to screen of 116 for men and 180 for women. Conclusions Using both polygenic risk scores and primary care records to prioritize individuals at highest risk of a CVD event for a formal CVD risk assessment can efficiently prioritize those who need interventions the most than using primary care records alone. This could lead to better allocation of resources by reducing the number of risk assessments in primary care while still preventing the same number of CVD events.

A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.

Objectives: REVEAL-CKD aims to estimate the prevalence of, and factors associated with, undiagnosed stage 3 chronic kidney disease (CKD)., Design: Multinational, observational study., Setting: Data from six country-specific electronic medical records and/or insurance claims databases from five countries (France, Germany, Italy, Japan and the USA [two databases])., Participants: Eligible participants (≥18 years old) had ≥2 consecutive estimated glomerular filtration rate (eGFR) measurements (calculated from serum creatinine values, sex and age) taken from 2015 onwards that were indicative of stage 3 CKD (≥30 and <60 mL/min/1.73 m 2 ). Undiagnosed cases lacked an International Classification of Diseases 9/10 diagnosis code for CKD (any stage) any time before, and up to 6 months after, the second qualifying eGFR measurement (study index)., Main Outcome Measures: The primary outcome was point prevalence of undiagnosed stage 3 CKD. Time to diagnosis was assessed using the Kaplan-Meier approach. Factors associated with lacking a CKD diagnosis and risk of diagnostic delay were assessed using logistic regression adjusted for baseline covariates., Results: The prevalence of undiagnosed stage 3 CKD was 95.5% (19 120/20 012 patients) in France, 84.3% (22 557/26 767) in Germany, 77.0% (50 547/65 676) in Italy, 92.1% (83 693/90 902) in Japan, 61.6% (13 845/22 470) in the US Explorys Linked Claims and Electronic Medical Records Data database and 64.3% (161 254/250 879) in the US TriNetX database. The prevalence of undiagnosed CKD increased with age. Factors associated with undiagnosed CKD were female sex (vs male, range of odds ratios across countries: 1.29-1.77), stage 3a CKD (vs 3b, 1.81-3.66), no medical history (vs a history) of diabetes (1.26-2.77) or hypertension (1.35-1.78)., Conclusions: There are substantial opportunities to improve stage 3 CKD diagnosis, particularly in female patients and older patients. The low diagnosis rates in patients with comorbidities that put them at risk of disease progression and complications require attention., Trial Registration: NCT04847531., Competing Interests: Competing interests: SB, EP, HC, KJ, and EW are employees of AstraZeneca and hold stock options. MA is an employee of AstraZeneca. NT has received grants from AstraZeneca, Boehringer 21 Ingelheim/Eli Lilly and Company, Janssen Pharmaceuticals, Otsuka Pharmaceutical Co, Ltd and Tricida, has received honoraria from AstraZeneca, Boehringer Ingelheim/Eli Lilly and Company, Janssen Pharmaceuticals, Otsuka Pharmaceutical and Tricida and holds stock options from Mesentech, Rénibus Therapeutics, pulseData and Tricida. MPS has received advisory board fees and honoraria from AstraZeneca, Bayer AG, Vifor Pharma Group and Boehringer Ingelheim/Eli Lilly and Company. LDN has received fees for scientific consultation and/or lectures by Astellas Pharma, AstraZeneca, Mundipharma and Vifor Pharma Group. PK has received speaker’s bureau and advisory board fees from AstraZeneca, Eli Lilly and Company and Novo Nordisk A/S, speaker’s fees from Bayer AG and honoraria from AstraZeneca and Eli Lilly and Company. TM and JBV have no conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Further understanding of adverse clinical event rates in patients with chronic kidney disease (CKD) is required for improved quality of care. This study described baseline characteristics, adverse clinical event rates, and mortality risk in patients with CKD, accounting for CKD stage and dialysis status., Methods: This retrospective, noninterventional cohort study included data from adults (aged ≥ 18 years) with two consecutive estimated glomerular filtration rates of < 60 ml/min/1.73 m 2 , recorded ≥ 3 months apart, from the UK Clinical Practice Research Datalink of electronic health records obtained between January 1, 2004, and December 31, 2017. Select adverse clinical events, associated with CKD and difficult to quantify in randomized trials, were assessed; defined by Read codes and International Classification of Diseases, Tenth Revision codes. Clinical event rates were assessed by dialysis status (dialysis-dependent [DD], incident dialysis-dependent [IDD], or non-dialysis-dependent [NDD]), dialysis modality (hemodialysis [HD] or peritoneal dialysis [PD]), baseline NDD-CKD stage (3a-5), and observation period., Results: Overall, 310,953 patients with CKD were included. Comorbidities were more common in patients receiving dialysis than in NDD-CKD, and increased with advancing CKD stage. Rates of adverse clinical events, particularly hyperkalemia and infection/sepsis, also increased with advancing CKD stage and were higher in patients on HD versus PD. Mortality risk during follow-up (1-5-year range) was lowest in patients with stage 3a NDD-CKD (2.0-18.5%) and highest in patients with IDD-CKD (26.3-58.4%)., Conclusions: These findings highlight the need to monitor patients with CKD for comorbidities and complications, as well as signs or symptoms of clinical adverse events., (© 2023. The Author(s).)

Biological invasions are usually examined in the context of their impacts on native species. However, few studies have examined the dynamics between invaders when multiple exotic species successfully coexist in a novel environment. Yet, long-term coexistence of now established exotic species has been observed in North American lady beetle communities. Exotic lady beetles Harmonia axyridis and Coccinella septempunctata were introduced for biological control in agricultural systems and have since become dominant species within these communities. In this study, we investigated coexistence via spatial and temporal niche partitioning among H. axyridis and C. septempunctata using a 31-year data set from southwestern Michigan, USA. We found evidence of long-term coexistence through a combination of small-scale environmental, habitat, and seasonal mechanisms. Across years, H. axyridis and C. septempunctata experienced patterns of cyclical dominance likely related to yearly variation in temperature and precipitation. Within years, populations of C. septempunctata peaked early in the growing season at 550 degree days, while H. axyridis populations grew in the season until 1250 degree days and continued to have high activity after this point. C. septempunctata was generally most abundant in herbaceous crops, whereas H. axyridis did not display strong habitat preferences. These findings suggest that within this region H. axyridis has broader habitat and abiotic environmental preferences, whereas C. septempunctata thrives under more specific ecological conditions. These ecological differences have contributed to the continued coexistence of these two invaders. Understanding the mechanisms that allow for the coexistence of dominant exotic species contributes to native biodiversity conservation management of invaded ecosystems., (© 2023 The Authors. Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

This study is a qualitative case series of lifestyle medicine practitioners' protocols for medication de-escalation in the context of reduced need for glucose-lowering medications due to lifestyle modifications. Increasing numbers of lifestyle medicine practitioners report achieving reductions in medications among patients with type 2 diabetes, and in some cases remission, but limited data exist on the clinical decision-making process used to determine when and how medications are deprescribed. Practitioners interviewed here provide accounts of their deprescribing protocols. This information can serve as pilot data for other practitioners seeking examples of how deprescribing in the context of lifestyle medicine treatment is conducted., Competing Interests: No potential conflicts of interest relevant to this article were reported., (© 2023 by the American Diabetes Association.)

Introduction: It is well established that chronic kidney disease (CKD) results in a significant burden on patients' health and health care providers. However, detailed estimates of the health care resource utilization (HCRU) of CKD are limited, particularly those which consider severity, comorbidities, and payer type. This study aimed to bridge this evidence gap by reporting contemporary HCRU and costs in patients with CKD across the US health care providers., Methods: Cost and HCRU estimates of CKD and reduced kidney function without CKD (estimated glomerular filtration rate [eGFR]: 60-75 and urine albumin-to-creatinine ratio [UACR]: <30) were derived for US patients included in the DISCOVER CKD cohort study, using linked inpatient and outpatient data from the limited claims-EMR data set (LCED) and TriNetX database. Patients with a history of transplant or undergoing dialysis were not included. HCRU and costs were stratified by CKD severity using UACR and eGFR., Results: Overall health care costs ranged from $26,889 (A1) to $42,139 (A3), and from $28,627 (G2) to $42,902 (G5) per patient per year (PPPY), demonstrating a considerable early disease burden which continued to increase with declining kidney function. The PPPY costs of later stage CKD were particularly notable for patients with concomitant heart failure ($50,191 [A3]) and those covered by commercial payers ($55,735 [A3])., Conclusions: Health care costs and resource use associated with CKD and reduced kidney function pose a substantial burden across health care systems and payers, increasing in line with CKD progression. Early CKD screening, particularly of UACR, paired with proactive disease management may provide both an improvement to patient outcomes and a significant HCRU and cost saving to health care providers., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Background: Hyperkalemia (HK) is a barrier to optimization of renin-angiotensin-aldosterone system inhibitor (RAASi) therapy in heart failure (HF) and chronic kidney disease (CKD). We investigated cardiorenal risk associated with changes in RAASi regimen after an episode of HK in patients with HF and/or CKD., Methods: This observational study utilized data from hospital records, claims, and health registers from the US (Optum's de-identified Market Clarity Data) and Japan (Medical Data Vision). Included patients had an index episode of HK between July 2019 and September 2021 (US), or May 2020 and September 2021 (Japan), with prior diagnosis of HF or CKD (stage 3 or 4), and RAASi use. Risk of a cardiorenal composite outcome (HF emergency visit, HF hospitalization, or progression to end-stage kidney disease) was determined in patients who discontinued RAASi, down-titrated their dose by > 25%, or maintained or up-titrated their dose following the HK episode., Results: A total of 15,488 and 6020 patients were included from the US and Japan, respectively. Prior to the episode of HK, 59% (US) and 27% (Japan) of patients had achieved > 50% target RAASi dose. Following the episode of HK, 33% (US) and 32% (Japan) of patients did not fill a new RAASi prescription. Risk of the cardiorenal outcome at 6 months was higher in patients who discontinued or down-titrated versus maintained or up-titrated RAASi treatment both in the US (17.5, 18.3, and 10.6%; p <  0.001) and in Japan (19.7, 20.0, and 15.1%; p <  0.001)., Conclusion: HK-related RAASi discontinuation or down-titration was associated with higher risk of cardiorenal events versus maintained or up-titrated RAASi., (© 2023. The Author(s).)

Objectives: During COVID-19 vaccination programmes, new safety signals have emerged for vaccines, including extremely rare cases of thrombosis with thrombocytopaenia syndrome (TTS). Background event rates before and during the pandemic are essential for contextualisation of such infrequent events. In the literature, most studies do not report an overall TTS event rate. Rather, background rates are mainly reported for subtypes of thrombotic/thromboembolic diagnoses included in the TTS clinical definition mostly by anatomical location, with reported rates for TTS subtypes varying widely. The objective of this study was to report prepandemic TTS background event rates in the general population., Methods: Prepandemic background TTS rates were generated via secondary data analysis using a cohort design in the IBM Truven MarketScan (now Merative MarketScan) US health insurance claims database, from 1 January 2019 to 31 December 2019. Two algorithms were applied: thrombocytopaenia occurring±7 days (algorithm 1) or occurring 1 day prior to ≤14 days after the thrombotic/thromboembolic event (algorithm 2)., Results: The study population derived from the MarketScan database analysis included approximately 9.8 million adults (aged ≥18 years; mean age 45 years, 52% females). Using this study population, prepandemic background TTS incidence was estimated as 9.8-11.1 per 100 000 person-years. Event rates were higher in males and increased with age. Similar patterns were observed with both algorithms., Conclusions: This study presents an estimate of aggregate prepandemic background TTS event rates including by type of thrombosis/thromboembolism and age group. The background event rates are dependent on the precision of capturing underlying TTS events in variable data sources, and the ability of electronic health records or insurance claims databases to reflect the TTS clinical definition. Differences between reported event rates demonstrate that estimating background event rates for rare, unprecedented safety events is methodologically challenging., Competing Interests: Competing interests: SdL has received grants through his University from AstraZeneca for research into COVID-19 vaccination (RAVEN) and adverse events of interest following COVID-19 vaccination (ATTEST). Although not directly related to this study, he is director of the Oxford Royal College of General Practitioners Research and Surveillance Centre. RH has no conflicts to report. HM, JM, SK, MA, MN, and HGdS are employees of, and may or may not hold stock in, AstraZeneca., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cardiovascular disease (CVD) risk prediction models for individuals with type 2 diabetes are important tools to guide intensification of interventions for CVD prevention. We aimed to assess the added value of incorporating risk factors variability in CVD risk prediction for people with type 2 diabetes., Methods: We used electronic health records (EHRs) data from 83 910 adults with type 2 diabetes but without pre-existing CVD from the UK Clinical Practice Research Datalink for 2004-2017. Using a landmark-modelling approach, we developed and validated sex-specific Cox models, incorporating conventional predictors and trajectories plus variability of systolic blood pressure (SBP), total and high-density lipoprotein (HDL) cholesterol, and glycated haemoglobin (HbA1c). Such models were compared against simpler models using single last observed values or means., Results: The standard deviations (SDs) of SBP, HDL cholesterol and HbA1c were associated with higher CVD risk (P < 0.05). Models incorporating trajectories and variability of continuous predictors demonstrated improvement in risk discrimination (C-index = 0.659, 95% CI: 0.654-0.663) as compared with using last observed values (C-index = 0.651, 95% CI: 0.646-0.656) or means (C-index = 0.650, 95% CI: 0.645-0.655). Inclusion of SDs of SBP yielded the greatest improvement in discrimination (C-index increase = 0.005, 95% CI: 0.004-0.007) in comparison to incorporating SDs of total cholesterol (C-index increase = 0.002, 95% CI: 0.000-0.003), HbA1c (C-index increase = 0.002, 95% CI: 0.000-0.003) or HDL cholesterol (C-index increase= 0.003, 95% CI: 0.002-0.005)., Conclusion: Incorporating variability of predictors from EHRs provides a modest improvement in CVD risk discrimination for individuals with type 2 diabetes. Given that repeat measures are readily available in EHRs especially for regularly monitored patients with diabetes, this improvement could easily be achieved., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke., Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank., Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min -1 ·1.73 m -2 , compared with those with eGFR between 60 and 105 mL·min -1 ·1.73 m -2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min -1 ·1.73 m -2 , with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min -1 ·1.73 m -2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min -1 ·1.73 m -2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD., Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Objectives: To describe a flexible common data model (CDM) approach that can be efficiently tailored to study-specific needs to facilitate pooled patient-level analysis and aggregated/meta-analysis of routinely collected retrospective patient data from disparate data sources; and to detail the application of this CDM approach to the DISCOVER CKD retrospective cohort, a longitudinal database of routinely collected (secondary) patient data of individuals with chronic kidney disease (CKD)., Methods: The flexible CDM approach incorporated three independent, exchangeable components that preceded data mapping and data model implementation: (1) standardized code lists (unifying medical events from different coding systems); (2) laboratory unit harmonization tables; and (3) base cohort definitions. Events between different coding vocabularies were not mapped code-to-code; for each data source, code lists of labels were curated at the entity/event level. A study team of epidemiologists, clinicians, informaticists, and data scientists were included within the validation of each component., Results: Applying the CDM to the DISCOVER CKD retrospective cohort, secondary data from 1,857,593 patients with CKD were harmonized from five data sources, across three countries, into a discrete database for rapid real-world evidence generation., Conclusions: This flexible CDM approach facilitates evidence generation from real-world data within the DISCOVER CKD retrospective cohort, providing novel insights into the epidemiology of CKD that may expedite improvements in diagnosis, prognosis, early intervention, and disease management. The adaptable architecture of this CDM approach ensures scalable, fast, and efficient application within other therapy areas to facilitate the combined analysis of different types of secondary data from multiple, heterogeneous sources., Competing Interests: This manuscript, including medical writing and editorial support, was funded by AstraZeneca. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Post-marketing surveillance for COVID-19 vaccines during the pandemic identified an extremely rare thrombosis with thrombocytopenia syndrome (TTS) reported post-vaccination, requiring further characterisation to improve diagnosis and management., Methods: We searched the AstraZeneca Global Safety Database (through April 26, 2021) for cases with co-reported thrombocytopenia and thrombosis (using standardised MedDRA queries/high-level terms) following AZD1222 (ChAdOx1 nCoV-19). Cases were adjudicated by experts as 'typical','possible', 'no' or 'unknown' according to available TTS criteria. Additional confirmatory datasets (May 20-June 20, October 1-December 28) were evaluated., Findings: We identified 573 reports, including 273 (47.6 %) 'typical' and 171 (29.8 %) 'possible' TTS cases. Of these 444 cases, 275 (61.9 %) were female, median age was 50.0 years (IQR: 38.0-60.0). Cerebral venous sinus thrombosis was reported in 196 (44.1 %) cases, splanchnic venous thrombosis in 65 (14.6 %) and thromboses at multiple sites in 119 (26.8 %). Median time to onset was 12.0 days (IQR: 9.0-15.0). Comparison with a pre-pandemic reference population indicated higher rates of autoimmune disorders (13.8 %, 4.4 %), previous heparin therapy (7.4 %, 1.2 %), history of thrombosis (5.5 %, 1.4 %), and immune thrombocytopenia (6.1 %, 0.2 %). Fatality rate was 22.2 % (127/573) overall and 23.6 % (105/444) in 'typical'/'possible' TTS, which decreased from 39.0 % (60/154) in February/March to 15.5 % (45/290) in April. Overall patterns were similar in confirmatory datasets., Conclusions: The reporting rate of 'typical'/'possible' TTS post first-dose vaccination in this dataset is 7.5 per million vaccinated persons; few cases were reported after subsequent doses, including booster doses. Peak reporting coincided with media-driven attention. Medical history differences versus a reference population indicate potentially unidentified risk factors. The decreasing fatality rate correlates with increasing awareness and publication of diagnostic/treatment guidelines. Adjudication was hindered by unreported parameters, and an algorithm was developed to classify potential TTS cases; comprehensive reporting could help further improve definition and management of this extremely rare syndrome., Competing Interests: Declaration of Competing Interest MAL declares consultancy work for AstraZeneca in relation to AZD1222, including for the present analyses. SR is a previous employee of AstraZeneca (2006–2010) and declares consultancy work for AstraZeneca in relation to the present analyses. MY, LBF, NKS, JM, NF, MA, HGdS, PB and MN are employees of AstraZeneca and may hold stock and/or stock options. MN participates on a Data Safety Monitoring Board or Advisory Board at the Karolinska Institute., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic kidney disease (CKD) is widely reported to decrease quality of life, increase morbidity and mortality and cause increased healthcare resource utilisation (HCRU) as the disease progresses. However, there is a relative paucity of accurate and recent estimates of HCRU in this patient population. Our aim was to address this evidence gap by reporting HCRU and related costs in patients with CKD from the UK primary and secondary care settings., Methods: HCRU and cost estimates of CKD were derived for UK patients included in the DISCOVER CKD cohort study using clinical records from the Clinical Practice Research Datalink linked to external databases. Patients with a history of transplant or undergoing dialysis were not included. HCRU and costs were stratified by CKD severity using the urinary albumin:creatinine ratio (UACR) and estimated glomerular filtration rate., Results: Hospitalisation rates more than tripled between low (A1) and high (A3) UACR categories and the mean annual per-patient costs ranged from £4966 (A1) to £9196 (A3) and from £4997 (G2) to £7595 (G5), demonstrating that a large healthcare burden can be attributed to a relatively small number of patients with later stage CKD, including those with kidney failure and/or albuminuria., Conclusions: HCRU and costs associated with CKD impose a substantial burden on the healthcare system, particularly in the more advanced stages of CKD. New interventions that can delay the progression of CKD to kidney failure may not only prolong the patient's life, but would also provide significant resource and cost savings to healthcare providers., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Introduction: Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines classify chronic kidney disease (CKD) risk or prognosis using estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR). We assessed patient characteristics and outcomes according to the KDIGO classification, using data from DISCOVER CKD (NCT04034992)., Methods: Data were extracted from the US integrated Limited Claims and Electronic Health Record Dataset and TriNetX databases, and the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics databases. Eligible patients were aged ≥18 years with CKD, and identified by 2 consecutive eGFR measures (5 to <75 ml/min/1.73 m 2 ; ≥90 days apart [maximum 730]) from January 2008. Index date was the second eGFR measurement; patients were categorized using the UACR measure closest to the index. Outcomes included patient characteristics, eGFR or UACR measurement frequency, and clinical outcomes per baseline KDIGO classification., Results: Across databases, only 8.6% of patients with 2 eGFR measures had ≥1 UACR measures. Among 123,807 eligible patients, prevalence of heart failure, hypertension, and type 2 diabetes increased with increasing albuminuria. Incidence rates of mortality and adverse cardiovascular and renal outcomes increased with declining baseline eGFR, and particularly with increasing albuminuria. Median number of eGFR and UACR tests per year post-index ranged from 1.6 to 2.5 and 0.5 to 0.6, respectively, across databases; there was no clear increase in UACR testing frequency following the KDIGO 2012 guidelines., Conclusion: Albuminuria monitoring is critical for optimal risk stratification in CKD, and our findings highlight an imperative for more regular UACR testing in clinical practice., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Longitudinal cognitive testing is essential for developing novel preventive interventions for dementia and Alzheimer's disease; however, the few available tools have significant practice effect and depend on an external evaluator. We developed a self-administered 10-min at-home test intended for longitudinal cognitive monitoring, Boston Cognitive Assessment or BOCA. The goal of this project was to validate BOCA. BOCA uses randomly selected non-repeating tasks to minimize practice effects. BOCA evaluates eight cognitive domains: 1) Memory/Immediate Recall, 2) Combinatorial Language Comprehension/Prefrontal Synthesis, 3) Visuospatial Reasoning/Mental rotation, 4) Executive function/Clock Test, 5) Attention, 6) Mental math, 7) Orientation, and 8) Memory/Delayed Recall. BOCA was administered to patients with cognitive impairment (n = 50) and age- and education-matched controls (n = 50). Test scores were significantly different between patients and controls (p < 0.001) suggesting good discriminative ability. The Cronbach's alpha was 0.87 implying good internal consistency. BOCA demonstrated strong correlation with Montreal Cognitive Assessment (MoCA) (R = 0.90, p < 0.001). The study revealed strong (R = 0.94, p < 0.001) test-retest reliability of the total BOCA score one week after participants' initial administration. The practice effect tested by daily BOCA administration over 10 days was insignificant (β = 0.03, p = 0.68). The effect of the screen size tested by BOCA administration on a large computer screen and re-administration of the BOCA to the same participant on a smartphone was insignificant (β = 0.82, p = 0.17; positive β indicates greater score on a smartphone). BOCA has the potential to reduce the cost and improve the quality of longitudinal cognitive tracking essential for testing novel interventions designed to reduce or reverse cognitive aging. BOCA is available online gratis at www.bocatest.org ., (© 2022. The Author(s).)

Introduction: Real-world data reporting healthcare resource utilisation and costs associated with end-of-life care for patients with chronic kidney disease (CKD) are limited. We examined length of hospitalisation and costs associated with end-of-life inpatient encounters using retrospective data from DISCOVER CKD., Methods: Data on inpatient encounters for patients with CKD aged ≥ 18 years between January 2016 and March 2020 were extracted from the US Premier Hospital Database. Encounters ending in death were identified and grouped by reason for the encounter, using the International Classification of Diseases, Tenth Revision, and by their insurance coverage. Encounters were evaluated overall and stratified according to cardiovascular (CV), kidney failure and infection-related reasons, and by their coverage by commercial, Medicaid, Medicare or other insurers. Length of hospitalisation and total costs were calculated for encounters., Results: Among 237,734 encounters ending in death, the mean [standard deviation (SD)] age was 74.2 (12.4) years, and 45.3% of patients were female. In total, 25,118, 4210 and 76,307 encounters were classified as relating to CV reasons, kidney failure and infection, respectively. Among all encounters, the mean (SD) length of hospitalisation ranged from 9.1 (11.2) (Medicare) to 12.8 (18.4) (Medicaid) days. Across insurers, encounters related to kidney failure were associated with the longest hospitalisations compared with CV and infection [mean range (days): 10.7-15.9 vs. 7.5-10.5 and 8.7-12.7, respectively]. The median [interquartile range (IQR)] total cost of any inpatient encounter was $17,057 ($8040-35,873). Kidney failure-related encounters had higher costs compared with CV and infection [median (IQR), $18,469 ($8673-38,315) vs. $17,503 ($7766-39,693) and $16,403 ($7762-34,910), respectively]. Medicaid-covered encounters had the highest costs of all insurers [median (IQR), $16,189 ($7725-33,443)]., Conclusions: Among patients with CKD, end-of-life encounters were most frequently related to infection. Encounters relating to kidney failure incurred the highest costs., Trial Registration: ClinicalTrials.gov identifier: NCT04034992., (© 2022. The Author(s).)

The exogenous small interfering RNA (exo-siRNA) pathway is a key antiviral mechanism in the Aedes aegypti mosquito, a widely distributed vector of human-pathogenic arboviruses. This pathway is induced by virus-derived double-stranded RNAs (dsRNA) that are cleaved by the ribonuclease Dicer 2 (Dcr2) into predominantly 21 nucleotide (nt) virus-derived small interfering RNAs (vsiRNAs). These vsiRNAs are used by the effector protein Argonaute 2 within the RNA-induced silencing complex to cleave target viral RNA. Dcr2 contains several domains crucial for its activities, including helicase and RNase III domains. In Drosophila melanogaster Dcr2, the helicase domain has been associated with binding to dsRNA with blunt-ended termini and a processive siRNA production mechanism, while the platform-PAZ domains bind dsRNA with 3' overhangs and subsequent distributive siRNA production. Here we analyzed the contributions of the helicase and RNase III domains in Ae. aegypti Dcr2 to antiviral activity and to the exo-siRNA pathway. Conserved amino acids in the helicase and RNase III domains were identified to investigate Dcr2 antiviral activity in an Ae. aegypti-derived Dcr2 knockout cell line by reporter assays and infection with mosquito-borne Semliki Forest virus (Togaviridae, Alphavirus). Functionally relevant amino acids were found to be conserved in haplotype Dcr2 sequences from field-derived Ae. aegypti across different continents. The helicase and RNase III domains were critical for silencing activity and 21 nt vsiRNA production, with RNase III domain activity alone determined to be insufficient for antiviral activity. Analysis of 21 nt vsiRNA sequences (produced by functional Dcr2) to assess the distribution and phasing along the viral genome revealed diverse yet highly consistent vsiRNA pools, with predominantly short or long sequence overlaps including 19 nt overlaps (the latter representing most likely true Dcr2 cleavage products). Combined with the importance of the Dcr2 helicase domain, this suggests that the majority of 21 nt vsiRNAs originate by processive cleavage. This study sheds new light on Ae. aegypti Dcr2 functions and properties in this important arbovirus vector species., Competing Interests: The authors have declared that no competing interests exist.

Background: Timely diagnosis and treatment of stage 3 chronic kidney disease (CKD) can prevent further loss of kidney function and progression to kidney failure. However, contemporary data on the global prevalence of undiagnosed stage 3 CKD are scarce. REVEAL-CKD is a multinational, multifocal and observational study aiming to provide insights into undiagnosed stage 3 CKD in a large population., Methods: Patients (aged ≥18 years) with data in selected secondary databases from 11 countries will be included if they have at least two estimated glomerular filtration rate (eGFR) measurements from 2015 onwards that are ≥30 and <60 mL/min/1.73 m 2 , recorded >90 and ≤730 days apart. Undiagnosed cases are those without an International Classification of Diseases 9/10 diagnosis code for CKD (any stage) any time before and up to 6 months after the second qualifying eGFR measurement. Time to diagnosis will be assessed using a Kaplan-Meier approach; patient characteristics associated with undiagnosed CKD will be assessed using adjusted logistical regression analyses., Results: REVEAL-CKD will assess the point prevalence of undiagnosed stage 3 CKD and time to CKD diagnosis in initially undiagnosed cases overall and in individual countries. Trends in undiagnosed CKD prevalence by calendar year will be assessed. Patient characteristics, healthcare resource utilization, adverse clinical outcomes, and CKD management and monitoring practices in patients with versus without a CKD diagnosis will be compared., Conclusions: REVEAL-CKD will increase awareness of the global clinical and economic burden of undiagnosed stage 3 CKD and provide valuable insights to inform clinical practice and policy changes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

We theoretically and numerically study the efficiency of Brillouin-based opto-acoustic data storage in a photonic waveguide in the presence of thermal noise and laser phase noise. We compare the physics of the noise processes and how they affect different storage techniques, examining both amplitude and phase storage schemes. We investigate the effects of storage time and pulse properties on the quality of the retrieved signal and find that phase storage is less sensitive to thermal noise than amplitude storage.

Background: Power tools are an integral part of orthopaedic surgery but have the capacity to cause iatrogenic injury. With this systematic review, we aimed to investigate the prevalence of iatrogenic injury due to the use of power tools in orthopaedic surgery and to discuss the current methods that can be used to reduce injury., Methods: We performed a systematic review of English-language studies related to power tools and iatrogenic injuries using a keyword search in MEDLINE, Embase, PubMed, and Scopus databases. Exclusion criteria included injuries related to cast-saw use, temperature-induced damage, and complications not clearly related to power-tool use., Results: A total of 3,694 abstracts were retrieved, and 88 studies were included in the final analysis. Few studies and individual case reports looked directly at the prevalence of injury due to power tools. These included 2 studies looking at the frequency of vascular injury during femoral fracture fixation (0.49% and 0.2%), 2 studies investigating the frequency of vertebral artery injury during spinal surgery (0.5% and 0.08%), and 4 studies investigating vascular injury during total joint arthroplasty (1 study involving 138 vascular injuries in 124 patients, 2 studies noting 0.13% and 0.1% incidence, and 1 questionnaire sent electronically to surgeons). There are multiple methods for preventing damage during power-tool use. These include the use of robotics and simulation, specific drill settings, and real-time feedback techniques such as spectroscopy and electromyography., Conclusions: Power tools have the potential to cause iatrogenic injury to surrounding structures during orthopaedic surgery. Fortunately, the published literature suggests that the frequency of iatrogenic injury using orthopaedic power tools is low. There are multiple technologies available to reduce damage using power tools. In high-risk operations, the use of advanced technologies to reduce the chance of iatrogenic injury should be considered., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A336)., (Copyright © 2021 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

There is currently a great deal of interest in the use of nanoscale devices to emulate the behaviors of neurons and synapses and to facilitate brain-inspired computation. Here, it is shown that percolating networks of nanoparticles exhibit stochastic spiking behavior that is strikingly similar to that observed in biological neurons. The spiking rate can be controlled by the input stimulus, similar to "rate coding" in biology, and the distributions of times between events are log-normal, providing insights into the atomic-scale spiking mechanism. The stochasticity of the spiking behavior is then used for true random number generation, and the high quality of the generated random bit-streams is demonstrated, opening up promising routes toward integration of neuromorphic computing with secure information processing.

Cardiometabolic diseases are frequently polygenic in architecture, comprising a large number of risk alleles with small effects spread across the genome 1-3 . Polygenic scores (PGS) aggregate these into a metric representing an individual's genetic predisposition to disease. PGS have shown promise for early risk prediction 4-7 and there is an open question as to whether PGS can also be used to understand disease biology 8 . Here, we demonstrate that cardiometabolic disease PGS can be used to elucidate the proteins underlying disease pathogenesis. In 3,087 healthy individuals, we found that PGS for coronary artery disease, type 2 diabetes, chronic kidney disease and ischaemic stroke are associated with the levels of 49 plasma proteins. Associations were polygenic in architecture, largely independent of cis and trans protein quantitative trait loci and present for proteins without quantitative trait loci. Over a follow-up of 7.7 years, 28 of these proteins associated with future myocardial infarction or type 2 diabetes events, 16 of which were mediators between polygenic risk and incident disease. Twelve of these were druggable targets with therapeutic potential. Our results demonstrate the potential for PGS to uncover causal disease biology and targets with therapeutic potential, including those that may be missed by approaches utilizing information at a single locus., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Randomized trials of salt restriction have consistently demonstrated that decreasing salt consumption lowers blood pressure, but results of observational studies of salt intake and cardiovascular disease have been conflicting. After excluding individuals with prevalent cardiovascular or kidney disease in the prospective UK Biobank study, we examined the within-person variability in spot urinary sodium excretion and its impact on associations with systolic blood pressure and risk of incident cardiovascular disease. Spearman correlation coefficients were used to assess within-person variability in spot urinary sodium, and associations between sodium and blood pressure were assessed using linear regression in participants with measurements at baseline (N=355 134) and after 9 years (N=33 915). Cox regression was used to assess associations with the risk of cardiovascular disease over the same follow-up period (N=5566 events). The within-person variability in urinary sodium was extreme, with a self-correlation coefficient of 0.35 over 4 years. Each 100 mmol/L higher usual urinary sodium was associated with 3.09 mm Hg higher systolic blood pressure (95% CI, 2.7–3.48) at baseline, but had no association at 9 years (0.97 [−0.44 to 2.37]). Likewise, there was no association between urinary sodium and risk of cardiovascular disease over the same follow-up period (hazard ratio, 1.05, [0.87–1.26]). While spot urinary sodium measurements were associated with immediate effects on blood pressure at baseline, the extreme within-person variability in urinary sodium precluded detection of associations with future blood pressure at resurvey or risk of cardiovascular disease. The limitations of observational studies, irrespective of study size, should be recognized when assessing public policy on salt restriction.

Cardiovascular disease (CVD) risk-prediction models are used to identify high-risk individuals and guide statin initiation. However, these models are usually derived from individuals who might initiate statins during follow-up. We present a simple approach to address statin initiation to predict "statin-naive" CVD risk. We analyzed primary care data (2004-2017) from the UK Clinical Practice Research Datalink for 1,678,727 individuals (aged 40-85 years) without CVD or statin treatment history at study entry. We derived age- and sex-specific prediction models including conventional risk factors and a time-dependent effect of statin initiation constrained to 25% risk reduction (from trial results). We compared predictive performance and measures of public-health impact (e.g., number needed to screen to prevent 1 event) against models ignoring statin initiation. During a median follow-up of 8.9 years, 103,163 individuals developed CVD. In models accounting for (versus ignoring) statin initiation, 10-year CVD risk predictions were slightly higher; predictive performance was moderately improved. However, few individuals were reclassified to a high-risk threshold, resulting in negligible improvements in number needed to screen to prevent 1 event. In conclusion, incorporating statin effects from trial results into risk-prediction models enables statin-naive CVD risk estimation and provides moderate gains in predictive ability but had a limited impact on treatment decision-making under current guidelines in this population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Chronological age is the strongest risk factor for most chronic diseases. Developing a biomarker-based age and understanding its most important contributing biomarkers may shed light on the effects of age on later-life health and inform opportunities for disease prevention., Methods: A subpopulation of 141 254 individuals healthy at baseline were studied, from among 480 019 UK Biobank participants aged 40-70 recruited in 2006-2010, and followed up for 6-12 years via linked death and secondary care records. Principal components of 72 biomarkers measured at baseline were characterized and used to construct sex-specific composite biomarker ages using the Klemera Doubal method, which derived a weighted sum of biomarker principal components based on their linear associations with chronological age. Biomarker importance in the biomarker ages was assessed by the proportion of the variation in the biomarker ages that each explained. The proportions of the overall biomarker and chronological age effects on mortality and age-related hospital admissions explained by the biomarker ages were compared using likelihoods in Cox proportional hazard models., Results: Reduced lung function, kidney function, reaction time, insulin-like growth factor 1, hand grip strength, and higher blood pressure were key contributors to the derived biomarker age in both men and women. The biomarker ages accounted for >65% and >84% of the apparent effect of age on mortality and hospital admissions for the healthy and whole populations, respectively, and significantly improved prediction of mortality (p < .001) and hospital admissions (p < 1 × 10-10) over chronological age alone., Conclusions: This study suggests that a broader, multisystem approach to research and prevention of diseases of aging warrants consideration., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Real-world data for patients with chronic kidney disease (CKD), specifically pertaining to clinical management, metabolic control, treatment patterns, quality of life (QoL) and dietary patterns, are limited. Understanding these gaps using real-world, routine care data will improve our understanding of the challenges and consequences faced by patients with CKD, and will facilitate the long-term goal of improving their management and prognosis., Methods: DISCOVER CKD follows an enriched hybrid study design, with both retrospective and prospective patient cohorts, integrating primary and secondary data from patients with CKD from China, Italy, Japan, Sweden, the UK and the USA. Data will be prospectively captured over a 3-year period from >1000 patients with CKD who will be followed up for at least 1 year via electronic case report form entry during routine clinical visits and also via a mobile/tablet-based application, enabling the capture of patient-reported outcomes (PROs). In-depth interviews will be conducted in a subset of ∼100 patients. Separately, secondary data will be retrospectively captured from >2 000 000 patients with CKD, extracted from existing datasets and registries., Results: The DISCOVER CKD program captures and will report on patient demographics, biomarker and laboratory measurements, medical histories, clinical outcomes, healthcare resource utilization, medications, dietary patterns, physical activity and PROs (including QoL and qualitative interviews)., Conclusions: The DISCOVER CKD program will provide contemporary real-world insight to inform clinical practice and improve our understanding of the epidemiology and clinical and economic burden of CKD, as well as determinants of clinical outcomes and PROs from a range of geographical regions in a real-world CKD setting., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: The number of gluten-free diet followers without celiac disease (CD) is increasing. However, little is known about the characteristics of these individuals., Objectives: We address this issue by investigating a wide range of genetic and phenotypic characteristics in association with following a gluten-free diet., Methods: The cross-sectional association between lifestyle and health-related characteristics and following a gluten-free diet was investigated in 124,447 women and men aged 40-69 y from the population-based UK Biobank study. A genome-wide association study (GWAS) of following a gluten-free diet was performed., Results: A total of 1776 (1.4%) participants reported following a gluten-free diet. Gluten-free diet followers were more likely to be women, nonwhite, highly educated, living in more socioeconomically deprived areas, former smokers, have lost weight in the past year, have poorer self-reported health, and have made dietary changes as a result of illness. Conversely, these individuals were less likely to consume alcohol daily, be overweight or obese, have hypertension, or use cholesterol-lowering medication. Participants with hospital inpatient diagnosed blood and immune mechanism disorders (OR: 1.62; 95% CI: 1.18, 2.21) and non-CD digestive system diseases (OR: 1.58; 95% CI: 1.42, 1.77) were more likely to follow a gluten-free diet. The GWAS demonstrated that no genetic variants were associated with being a gluten-free diet follower., Conclusions: Gluten-free diet followers have a better cardiovascular risk profile than non-gluten-free diet followers but poorer self-reported health and a higher prevalence of blood and immune disorders and digestive conditions. Reasons for following a gluten-free diet warrant further investigation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Introduction: Nutritional intervention, such as a whole-food plant-based (WFPB) diet, is suggested to improve symptoms of autoimmune disorders. Its effects on neuromuscular junction (NMJ) diseases are less known. Case Description: A 56-year-old female with a combined myasthenia gravis and Lambert-Eaton myasthenic syndrome presented with persistent musculoskeletal weakness and pain, fatigue, and diminished concentration. Methods: A WFPB diet was implemented for 5 months in this case study. Functionality, biometrics, and quality of life were assessed at regular intervals via blood work, vital signs, and patient surveys. Results: After 10 weeks, 2 medications were de-prescribed due to improvement in blood glucose levels and blood pressure readings. Neuromuscular symptoms lessened as measured by the Myasthenia Gravis Illness Index. Weight loss of 18.7 pounds was achieved. No deterioration in physical activity was reported throughout the 5-month trial of WFPB diet. Discussion: Our results have implications that an individualized dietary strategy may be considered as one component of management of NMJ diseases. The effects of WFPB diet on NMJ diseases remain inconclusive., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 The Author(s).)

We theoretically and numerically study the effects of thermal noise on pulses in backwards stimulated Brillouin scattering (SBS). Using a combination of stochastic calculus and numerical methods, we derive a theoretical model that can be used to quantitatively predict noise measurements. We study how the optical pulse configuration, including the input powers of the pump and Stokes fields, pulse durations and interaction time, affects the noise in the output Stokes field. We investigate the effects on the noise of the optical loss and waveguide length, and we find that the signal-to-noise ratio can be significantly improved, or reduced, for specific combinations of waveguide properties and pulse parameters.

Background: Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD., Methods and Findings: Using data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703-0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009-0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40-75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to <10%) 10-year CVD risk could help prevent 1 additional CVD event for approximately every 340 individuals screened. Such a targeted strategy could help prevent 7% more CVD events than conventional risk prediction alone. Potential gains afforded by assessment of PRSs on top of conventional risk factors would be about 1.5-fold greater than those provided by assessment of C-reactive protein, a plasma biomarker included in some risk prediction guidelines. Potential limitations of this study include its restriction to European ancestry participants and a lack of health economic evaluation., Conclusions: Our results suggest that addition of PRSs to conventional risk factors can modestly enhance prediction of first-onset CVD and could translate into population health benefits if used at scale., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SK is funded by grants to institution from: British Heart Foundation, UK Medical Research Council, UK National Institute of Health Research, Cambridge Biomedical Research Centre. SB is a paid statistical reviewer for PLOS Medicine. ASB received grants outside of this work from AstraZeneca, Biogen, Bioverativ, Merck, Novartis and Sanofi, as well as personal fees from Novartis. JD serves on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010), the Steering Committee of UK Biobank (since 2011), the MRC International Advisory Group (ING) member, London (since 2013), the MRC High Throughput Science ‘Omics Panel Member, London (since 2013), the Scientific Advisory Committee for Sanofi (since 2013), the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis and the Astra Zeneca Genomics Advisory Board (2018).