Mutational analysis of Aedes aegypti Dicer 2 provides insights into the biogenesis of antiviral exogenous small interfering RNAs.

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.

Mesoporous Metal Sponges Produced by Explosive Decomposition.

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 (χG) 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 χG ≈0.65. In broad agreement with experiment, sponge formation in the simulations is bounded by stoichiometry; no sponges form if χG is <0.52, for χG between 0.52 and 0.70 the sponge is characterized by vermicular cavities whereas classic bicontinuous fibrous sponges form for 0.70< χG < 0.85 and, finally, discrete particles result if χG >0.85.

Hyperkalaemia-related reduction of RAASi treatment associates with more subsequent inpatient care.

BACKGROUND: Hyperkalaemia is a barrier to achieving optimal, guideline-directed treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with chronic kidney disease (CKD) and/or heart failure (HF). This study describes the association between hyperkalaemia-related RAASi treatment reduction and 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 RAASi 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 before versus after 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 (95% confidence intervals) increased by 18.2 (17.0-19.2) days per person-year in Sweden and 17.9 (17.4-18.5) days per person-year in Japan among patients with reduced RAASi treatment compared with increases of 9.4 (8.6-10.4) and 8.5 (8.0-9.0) days per person-year, respectively, among patients with maintained RAASi treatment. Mean (standard deviation) DAOH were 121.5 (75.0) in Sweden and 141.7 (54.5) in Japan among patients with reduced RAASi treatment compared with 154.0 (51.3) and 157.5 (31.6) days, 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.

Computation via Neuron-like Spiking in Percolating Networks of Nanoparticles.

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.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

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.

Rates of adverse clinical events in patients with chronic kidney disease: analysis of electronic health records from the UK clinical practice research datalink linked to hospital data.

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 m2, 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.

Clinical impact of suboptimal RAASi therapy following an episode of hyperkalemia.

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.

Medication Deprescribing Among Patients With Type 2 Diabetes: A Qualitative Case Series of Lifestyle Medicine Practitioner Protocols.

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.

Surgical treatment of ankle instability in children with os subfibulare.

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.

Boston cognitive assessment (BOCA) - a comprehensive self-administered smartphone- and computer-based at-home test for longitudinal tracking of cognitive performance.

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 (ß = 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 (ß = 0.82, p = 0.17; positive ß 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 .

Polygenic risk scores in cardiovascular risk prediction: A cohort study and modelling analyses.

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.

Prediction of Cardiovascular Disease Risk Accounting for Future Initiation of Statin Treatment.

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.

Noise and pulse dynamics in backward stimulated Brillouin scattering.

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.

Noise in Brillouin based information storage.

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.

Atomic Scale Dynamics Drive Brain-like Avalanches in Percolating Nanostructured Networks.

Self-assembled networks of nanoparticles and nanowires have recently emerged as promising systems for brain-like computation. Here, we focus on percolating networks of nanoparticles which exhibit brain-like dynamics. We use a combination of experiments and simulations to show that the brain-like network dynamics emerge from atomic-scale switching dynamics inside tunnel gaps that are distributed throughout the network. The atomic-scale dynamics emulate leaky integrate and fire (LIF) mechanisms in biological neurons, leading to the generation of critical avalanches of signals. These avalanches are quantitatively the same as those observed in cortical tissue and are signatures of the correlations that are required for computation. We show that the avalanches are associated with dynamical restructuring of the networks which self-tune to balanced states consistent with self-organized criticality. Our simulations allow visualization of the network states and detailed mechanisms of signal propagation.

Munc18a clusters SNARE-bearing liposomes prior to trans-SNARE zippering.

Sec1-Munc18 (SM) proteins co-operate with SNAREs {SNAP [soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein] receptors} to mediate membrane fusion in eukaryotic cells. Studies of Munc18a/Munc18-1/Stxbp1 in neurotransmission suggest that SM proteins accelerate fusion kinetics primarily by activating the partially zippered trans-SNARE complex. However, accumulating evidence has argued for additional roles for SM proteins in earlier steps in the fusion cascade. Here, we investigate the function of Munc18a in reconstituted exocytic reactions mediated by neuronal and non-neuronal SNAREs. We show that Munc18a plays a direct role in promoting proteoliposome clustering, underlying vesicle docking during exocytosis. In the three different fusion reactions examined, Munc18a-dependent clustering requires an intact N-terminal peptide (N-peptide) motif in syntaxin that mediates the binary interaction between syntaxin and Munc18a. Importantly, clustering is preserved under inhibitory conditions that abolish both trans-SNARE complex formation and lipid mixing, indicating that Munc18a promotes membrane clustering in a step that is independent of trans-SNARE zippering and activation.

Extending the applicability of the four-flux radiative transfer method.

A generalized four-flux method capable of modeling and tuning the spectral reflectance of a diverse range of complex composite coatings is presented. An example application is exploring and maximizing the visible and near-infrared (IR) spectral reflectance available from the diverse structures arising from combinations of the many practical paint ingredients that are available or can be made when applied to different substrates. This requires consideration of scatterers that can differ in composition, particle size, size distribution, and fill factor, and are held in place by a variety of organic binders, which typically partially absorb in the near IR. This extended model is further enhanced by an explicit matrix algorithm that allows analysis of diverse multilayer stacks. This is applied to a multilayer and is designed to model useful changes that result from varying the pigment fill factor as a function of depth within a layer. What we believe is a novel feature is the way the scattering affects matrix absorptance. The model includes contributions to total absorptance from the scattering pigments and from the paint binder that can arise in different bands or simultaneously at the same wavelengths. Model accuracy is demonstrated by example results when compared to experimental data on dried single layer paint profiles using imaged cross sections. The model input covering the actual pigment and binder properties used are material, shape, size, and size distributions, mass added, and the measured optical constants from 400 nm to 2,500 nm of the undoped binder resin layer. One interesting result is the comparison of a two-layered stack, with bigger particles in the first layer and smaller ones in the second, to one with the opposite depth profile.

Multipolar and dark-mode plasmon resonances on drilled silver nano-triangles.

Dark-mode plasmon resonances can be excited by positioning a suitable nano-antenna above a nanostructure to couple a planar incident wave-front into a virtual point source. We explore this phenomenon using a prototypical nanostructure consisting of a silver nanotriangle into which a hole has been drilled and a rod-like nano-antenna of variable aspect ratio. Using numerical simulations, we establish the behavior of the basic drilled nanotriangle under plane wave illumination and electron beam irradiation to provide a baseline, and then add the nano-antenna to investigate the stimulation of additional dark-mode plasmon resonances. The introduction of a suitably tuned nano-antenna provides a new and general means of exciting dark-mode resonances using plane wave light. The resulting system exhibits a very rich variety of radiant and sub-radiant resonance modes.

Local plasmon resonances of metal-in-metal core-shells.

We investigate the tunability and strength of the localized surface plasmons of binary metal-in-metal core-shells. Ellipsoids are used as an analytical model to show how the fill factor continuously tunes a hybridized mode between those of the constituents, suggesting the use of metal combinations with widely differing plasma frequencies for broad tunability. A quasistatic eigenmode method is used separate geometric and material parameters to facilitate prediction of hybridized dipole modes in arbitrary shapes. A modified ellipsoid model is found to adequately describe the symmetric dipole-dipole resonance of well-rounded cuboids.