Target Range Research Articles

A Review of Probe-Based Enrichment Methods to Inform Plant Virus Diagnostics.

Modern diagnostic techniques based on DNA sequence similarity are currently the gold standard for the detection of existing and emerging pathogens. Whilst individual assays are inexpensive to use, assay development is costly and carries risks of not being sensitive or specific enough to capture an increasingly diverse range of targets. Sequencing can provide the entire nucleic acid content of a sample and may be used to identify all pathogens present in the sample when the depth of coverage is sufficient. Targeted enrichment techniques have been used to increase sequence coverage and improve the sensitivity of detection within virus samples, specifically, to capture sequences for a range of different viruses or increase the number of reads from low-titre virus infections. Vertebrate viruses have been well characterised using in-solution hybridisation capture to target diverse virus families. The use of probes for genotyping and strain identification has been limited in plants, and uncertainty around sensitivity is an impediment to the development of a large-scale virus panel to use within regulatory settings and diagnostic pipelines. This review aims to compare significant studies that have used targeted enrichment of viruses to identify approaches to probe design and potential for use in plant virus detection and characterisation.

Unlocking Potential: Personalized Lifestyle Therapy for Type 2 Diabetes Through a Predictive Algorithm-Driven Digital Therapeutic.

We present a digital therapeutic (DTx) using continuous glucose monitoring (CGM) and an advanced artificial intelligence (AI) algorithm to digitally personalize lifestyle interventions for people with type 2 diabetes (T2D). A study of 118 participants with non-insulin-treated T2D (HbA1c ≥ 6.5%) who were already receiving standard care and had a mean baseline (BL) HbA1c of 7.46% (0.93) used the DTx for three months to evaluate clinical endpoints, such as HbA1c, body weight, quality of life and app usage, for a pre-post comparison. The study also included an assessment of initial long-term data from a second use of the DTx. After three months of using the DTx, there was an improvement of 0.67% HbA1c in the complete cohort and -1.08% HbA1c in patients with poorly controlled diabetes (BL-HbA1c ≥ 7.0%) compared with standard of care (P < .001). The number of patients within the therapeutic target range (< 7.0%) increased from 38% to 60%, and 33% were on the way to remission (< 6.5%). Patients who used the DTx a second time experienced a reduction of -0.76% in their HbA1c levels and a mean weight loss of -6.84 kg after six months (P < .001) compared with BL. These results indicate that the DTx has clinically relevant effects on glycemic control and weight reduction for patients with both well and poorly controlled diabetes, whether through single or repeated usage. It is a noteworthy improvement in T2D management, offering a non-pharmacological, fully digital solution that integrates biofeedback through CGM and an advanced AI algorithm.

Lithium Ions as Modulators of Complex Biological Processes: The Conundrum of Multiple Targets, Responsiveness and Non-Responsiveness, and the Potential to Prevent or Correct Dysregulation of Systems during Aging and in Disease.

Lithium is one of the lightest elements on Earth and it has been in the environment since the formation of the galaxy. While a common element, it has not been found to be an essential element in biological processes, ranging from single cell organisms to Homo sapiens. Instead, at an early stage of evolution, organisms committed to a range of elements such as sodium, potassium, calcium, magnesium, zinc, and iron to serve essential functions. Such ions serve critical functions in ion channels, as co-factors in enzymes, as a cofactor in oxygen transport, in DNA replication, as a storage molecule in bone and liver, and in a variety of other roles in biological processes. While seemingly excluded from a major essential role in such processes, lithium ions appear to be able to modulate a variety of biological processes and "correct" deviation from normal activity, as a deficiency of lithium can have biological consequences. Lithium salts are found in low levels in many foods and water supplies, but the effectiveness of Li salts to affect biological systems came to recent prominence with the work of Cade, who reported that administrating Li salts calmed guinea pigs and was subsequently effective at relatively high doses to "normalize" a subset of patients with bipolar disorders. Because of its ability to modulate many biological pathways and processes (e.g., cyclic AMP, GSK-3beta, inositol metabolism, NaK ATPases, neuro processes and centers, immune-related events, respectively) both in vitro and in vivo and during development and adult life, Li salts have become both a useful tool to better understand the molecular regulation of such processes and to also provide insights into altered biological processes in vivo during aging and in disease states. While the range of targets for lithium action supports its possible role as a modulator of biological dysregulation, it presents a conundrum for researchers attempting to elucidate its specific primary target in different tissues in vivo. This review will discuss aspects of the state of knowledge regarding some of the systems that can be influenced, focusing on those involving neural and autoimmunity as examples, some of the mechanisms involved, examples of how Li salts can be used to study model systems, as well as suggesting areas where the use of Li salts could lead to additional insights into both disease mechanisms and natural processes at the molecular and cell levels. In addition, caveats regarding lithium doses used, the strengths and weaknesses of rodent models, the background genetics of the strain of mice or rats employed, and the sex of the animals or the cells used, are discussed. Low-dose lithium may have excellent potential, alone or in combination with other interventions to prevent or alleviate aging-associated conditions and disease progression.

Effectiveness of tenapanor for treating hyperphosphatemia in patients receiving dialysis: a plain language summary of the OPTIMIZE study

Plain Language Summary What is this summary about? This summary provides a review of the OPTIMIZE study, the results of which were published in Kidney360 in February 2024. The OPTIMIZE study looked at how well tenapanor tablets work to treat patients receiving dialysis who have high levels of phosphate in their blood, a condition called hyperphosphatemia. In the OPTIMIZE study, researchers wanted to understand if tenapanor would decrease phosphate levels in the blood to the target range. They also tested different ways of starting tenapanor treatment in patients. In the human body, kidneys are organs that filter blood and remove waste products. In chronic kidney disease, sometimes referred to as CKD, a patient’s kidneys do not work as well at filtering their blood and removing waste products. This can allow phosphate to build up in the blood. Phosphate levels may remain high despite patients receiving treatment such as dialysis, using pills that keep phosphate in the intestines (called phosphate binders) to prevent phosphate from being absorbed into the blood, and eating a low-phosphate diet. Phosphate levels may remain high despite these treatments because they can be difficult to follow. Most people receiving dialysis take 7–8 phosphate binder pills every day, and over half of those people have reported skipping at least one dose in the past month. Additionally, low-phosphate diets can be difficult to follow and people often struggle to meet their other nutritional needs. What are the key takeaways? Tenapanor used in combination with phosphate binders led to lower phosphate levels in the blood with the use of fewer phosphate-lowering pills. Tenapanor also lowered phosphate levels in patients who were not previously on phosphate binders but needed phosphate-lowering treatment. What were the main conclusions reported by the researchers? Tenapanor can help patients receiving dialysis better control their hyperphosphatemia. This is an abstract of the Plain Language Summary of Publication article. View the full Plain Language Summary PDF of this article to read the full-text Link to original article here

Evaluation of target area under the concentration-time curve of vancomycin in an initial dosing design: a retrospective cohort study.

Area under the concentration-time curve (AUC)-guided dosing of vancomycin was introduced in a clinical setting; however, the target range of non-steady-state AUCs, such as Day 1 AUC and Day 2 AUC, remains controversial. Therefore, we sought to determine pharmacokinetic parameter thresholds and identify independent risk factors associated with acute kidney injury (AKI) to establish a safe initial dosing design for vancomycin administration. A single-centre, retrospective, cohort study of hospitalized patients treated with vancomycin was conducted to determine the threshold of both non-steady-state AUCs (Day 1 and 2 AUCs) and trough levels at the first blood sampling point (therapeutic drug monitoring, TDM). In addition, independent risk factors associated with AKI were evaluated using univariate and multivariate logistic regression analyses. The thresholds for predicting AKI were estimated as 456.6 mg·h/L for AUC0-24h, 554.8 mg·h/L for AUC24-48h, 1080.8 mg·h/L for AUC0-48h and 14.0 μg/mL for measured trough levels, respectively. In a multivariate analysis, Day 2 AUC ≥ 554.8 mg·h/L [adjusted odds ratio (OR), 57.16; 95% confidence interval (CI), 11.95-504.05], piperacillin/tazobactam (adjusted OR, 15.84; 95% CI, 2.73-127.70) and diuretics (adjusted OR, 4.72; 95% CI, 1.13-21.01) were identified as risk factors for AKI. We identified thresholds for both AUCs in the non-steady-state and trough levels at the first TDM. Our results highlight the importance of monitoring not only the AUC but also trough levels during vancomycin treatment to reduce the likelihood of AKI.

Range-Velocity Measurement Accuracy Improvement Based on Joint Spatiotemporal Characteristics of Multi-Input Multi-Output Radar

For time division multiplexing multiple input multiple output (TDM MIMO) millimeter wave radar, the measurement of target range, velocity and other parameters depends on the phase of the received Intermediate Frequency (IF) signal. The coupling between range and velocity phases occurs when measuring moving targets, leading to inevitable errors in calculating range and velocity from the phase, which in turn affects measurement accuracy. Traditional two-dimensional fast fourier transform (2D FFT) estimation errors are particularly pronounced at high velocity, significantly impacting measurement accuracy. Additionally, due to limitations imposed by the Nyquist sampling theorem, there is a restricted range for velocity measurements that can result in aliasing. In this study, we propose a method to address the coupling of range and velocity based on the original signal as well as a method for velocity compensation to resolve aliasing issues. Our research findings demonstrate that this approach effectively reduces errors in measuring ranges and velocities of high-velocity moving targets while efficiently de-aliasing velocities.

Clinical and functional studies of MTOR variants in Smith-Kingsmore syndrome reveal deficits of circadian rhythm and sleep-wake behavior

Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent nine MTOR pathogenic variants. We conducted a detailed natural history study and found pathophysiological deficits among individuals with SKS in addition to the common neurodevelopmental symptoms. These symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, indicative of homeostatic imbalance. To characterize these variants, we developed cell models and characterized their functional consequences. We showed that these SKS variants display a range of mechanistic target of rapamycin (mTOR) activities and respond to the mTOR inhibitor, rapamycin, differently. For example, the R1480_C1483del variant we identified here and the previously known C1483F are more active than wild-type controls and less responsive to rapamycin. Further, we showed that SKS mutations dampened circadian rhythms and low-dose rapamycin improved the rhythm amplitude, suggesting that optimal mTOR activity is required for normal circadian function. As SKS is caused by gain-of-function mutations in MTOR, rapamycin was used to treat several patients. While higher doses of rapamycin caused delayed sleep-wake phase disorder in a subset of patients, optimized lower doses improved sleep. Our study expands the clinical and molecular spectrum of SKS and supports further studies for mechanism-guided treatment options to improve sleep-wake behavior and overall health.

Case report of pharmacokinetic analysis of continuous intravenous infusion of fentanyl in a patient with severe burn: burn shock stage complicates pain management

BackgroundFentanyl is widely used as an analgesic and sedative for patients with severe burn injuries in intensive care units. However, pharmacokinetic (PK) data for fentanyl, particularly for continuous intravenous infusion during the acute phase of burn injuries, are limited. Here, we report the clinical course and changes in blood fentanyl concentrations during the acute phase in a patient with severe burns treated with continuous intravenous infusion of fentanyl.Case presentationA woman in her 40s, with burns caused by a gas cylinder explosion, was transported to our hospital. The patient had burn wounds on face, neck, shoulders, and all four extremities, with a total burn area of 39.0%. For pain relief, the patient received a continuous infusion of 0.01 mg/mL fentanyl (20–30 µg/h) with a target blood concentration of 1.0–1.5 ng/mL, but continued to suffer from pain due to burning during the acute phase. We measured the blood fentanyl concentrations and found that all concentrations obtained during the acute phase were subtherapeutic. Notably, during the burn shock stage, blood concentrations of fentanyl were 0.50 ng/mL on day 1 and 0.66 ng/mL on day 2, indicating that the blood concentration did not rise sufficiently for the dosage. From days 0 to 2, the patient was administered a massive fluid load for burn shock. After the burn shock stage resolved, fentanyl concentrations gradually approached the target range, and the pain rating scale improved, even though the fentanyl administration rate remained unchanged (30 µg/h).ConclusionsMajor changes in the fluid volumes of body compartments that occur with large burns might increase the volume of fentanyl distribution, thereby lowering its concentration when a standard dose is administered. Our findings indicate that the PK of fentanyl in patients with severe burns can be substantially affected, especially during the shock phase, implying the importance of titrating analgesics for clinical efficacy in the acute phase.

Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration.

Macrocyclic drugs can address an increasing range of molecular targets but enabling central nervous system (CNS) access to these drugs has been viewed as an intractable problem. We designed and synthesized a series of quinolinium-modified cyclosporine derivatives targeted to the mitochondrial cyclophilin D protein. Modification of the cation to enable greater delocalization was confirmed by x-ray crystallography of the cations. Critically, greater delocalization improved brain concentrations. Assessment of the compounds in preclinical assays and for pharmacokinetics identified a molecule JP1-138 with at least 20 times the brain levels of a non-delocalized compound or those reported for cyclosporine. Levels were maintained over 24 hours together with low hERG potential. The paradigm outlined here could have widespread utility in the treatment of CNS diseases.

Comparison of Metabolic Control in Children and Adolescents Treated with Insulin Pumps.

While insulin pumps remain the most common form of therapy for youths with type 1 diabetes (T1DM), they differ in the extent to which they utilize data from continuous glucose monitoring (CGM) and automate insulin delivery. The aim of the study was to compare metabolic control in patients using different models of insulin pumps. This retrospective single-center study randomly sampled 30 patients for each of the following treatments: Medtronic 720G without PLGS (predictive low glucose suspend), Medtronic 640G or 740G with PLGS and Medtronic 780G. In the whole study group, we used CGM systems to assess patients' metabolic control, and we collected lipid profiles. In three groups of patients, we utilized CGM sensors (Guardian 3, Guardian 4, Libre 2 and Dexcom G6) to measure the following glycemic variability proxy values: time in range (TIR), time below 70 mg/dL (TBR), time above 180 mg/dL (TAR), coefficient of variation (CV) and mean sensor glucose. Medtronic 640G or 740G and 780G users were more likely to achieve a target time in the target range 70-180 mg/dL (≥80%) [Medtronic 720G = 4 users (13.3%) vs. Medtronic 640G/740G = 10 users (33.3%) vs. Medtronic 780G = 13 users (43.3%); p = 0.0357)] or low glucose variability [Medtronic 720G = 9 users (30%) vs. Medtronic 640G/740G = 18 users (60%) vs. Medtronic 780G = 19 users (63.3%); p = 0.0175)]. Any integration between the insulin pump and CGM was associated with better glycemic control. More advanced technologies and artificial intelligence in diabetes help patients maintain better glycemia by eliminating various factors affecting postprandial glycemia.

A New Methodology to Estimate the Early-Age Compressive Strength of Concrete before Demolding

Non-destructive testing has many advantages, such as the ability to obtain a large number of data without destroying existing structures. However, the reliability of the estimation accuracy and the limited range of applicable targets remain an issue. This study proposes a novel pin penetration test method to determine the early-age compressive strength of concrete before demolding. The timing of demolding and initial curing is determined according to the strength development of concrete. Therefore, it is important to determine the compressive strength at an early age before demolding at the actual construction site. The applicability of this strength estimation methodology at actual construction is investigated. Small test holes (12 mm in diameter) are prepared on the mold surface in real construction sites and mock-up specimens in advance. The pin is penetrated into these test holes to obtain the relationship between the compressive strength and the penetration depth. As a result, it is confirmed that the pin penetration test method is suitable for measuring the early-age compressive strength at the actual construction site. This allows the benchmark values for compressive strength, necessary to avoid early frost damage, to be directly verified on the concrete structural members at the construction site. For instance, the compressive strengths of greater than 5 MPa and 10 MPa can be confirmed by the penetration depths benchmark values of 8.0 mm and 6.7 mm or less, respectively.

The search for optimal nocturnal diurnal heart rate Index targets in ICU patients: a retrospective observational study from large ICU database.

Circadian rhythms play a crucial role in cardiovascular health, with the nocturnal diurnal heart rate index (NDHRI) reflecting significant circadian variations. However, the optimal NDHRI target in Intensive Care Unit (ICU) patients remains undefined. This study aims to establish an evidence-based NDHRI target range and assess its association with mortality. Data from the eICU Collaborative Research Database (n = 32,412) were analyzed. NDHRI was calculated by dividing cumulative nighttime heart rate area by daytime area. Generalized additive models (GAMs) explored the non-linear relationship between mean NDHRI and mortality, adjusting for confounders. Subgroup analyses were conducted based on ethnicity, ICU type, and comorbidities. A U-shaped association was observed between hospital mortality and mean NDHRI (P < 0.001). The optimal NDHRI range (40.0%-45.0%) demonstrated the lowest mortality rates. The duration spent within this range correlated inversely with mortality (P < 0.001). Subgroup analyses consistently supported these findings across diverse patient profiles. Our findings suggest an association between maintaining NDHRI within the 40.0%-45.0% range and lower mortality rates in critically ill patients, highlighting the potential utility of monitoring circadian heart rate variations in the ICU. Further research and future randomized controlled trials are essential to confirm causality and should consider this NDHRI range as a pivotal reference target.

Engineering miniature IscB nickase for robust base editing with broad targeting range.

IscB has a similar domain organization to Cas9, but the small size of IscB is better suited for delivery by adeno-associated virus. To improve the low editing efficiency of OgeuIscB (IscB from human gut metagenome) in mammalian cells, we developed high-efficiency miniature base editors by engineering OgeuIscB nickase and its cognate ωRNA, termed IminiBEs. We demonstrated the robust editing efficiency of IminiCBE (67% on average) or IminiABE (52% on average). Fusing non-specific DNA-binding protein Sso7d to IminiBEs increased the editing efficiency of low-efficiency sites by around two- to threefold, and we termed it SIminiBEs. In addition, IminiCBE and SIminiCBE recognize NNRR, NNRY and NNYR target-adjacent motifs, which broaden the canonical NWRRNA target-adjacent motif sites for the wild-type IscB nickase. Overall, IminiBEs and SIminiBEs are efficient miniature base editors for site-specific genomic mutations.

Are Surgical Outcomes Different According to Baseline Balance Status in Elderly Patients with Degenerative Sagittal Imbalance?

Retrospective study. We sought to compare surgical outcomes according to baseline balance statuses in elderly patients with degenerative sagittal imbalance (DSI). Although optimal sagittal correction has been emphasized for good surgical outcomes, the effect of the state of preoperative balance on surgical outcome has been adequately described at present. Patients aged ≥60 years with DSI who underwent ≥5-level fusion to the sacrum were included. Among them, only those who postoperatively achieved the optimal age-adjusted pelvic incidence (PI) - lumbar lordosis (LL) target were included in this study. Study participants were divided into two groups according to their preoperative sagittal vertical axis (SVA): compensatory balance (SVA <5cm, group CB) and decompensation (SVA ≥5cm, group D). Comparisons between the two groups were performed using the chi-squared test or Fisher's exact test for categorical variables and the independent t- test or Wilcoxon rank- sum test for continuous variables. A total of 156 patients whose postoperative sagittal alignment matched the age-adjusted PI-LL target constituted the study cohort. There were 59 patients in group CB and 97 patients in group D. Mean follow-up duration was 50.0 months after surgery. Immediate postoperatively, sacral slope and SVA were significantly greater in group D than in group CB. At last follow-up, the SVA was significantly greater in group D than in group CB (43.6 vs. 22.7mm), while no significant differences were found in other sagittal parameters. The Oswestry disability index and Scoliosis Research Society -22 scores at the last follow-up were significantly worse in group D than in group CB. The SVA tended to experience less correction postoperatively, with evidence of further deterioration during follow-up in group D than in group CB. This suboptimal correction of SVA may contribute to the inferior clinical outcomes encountered in group D relative to group CB. Therefore, we recommend correction of PI-LL as close as possible to the lower limit of the suggested PI-LL target range in patients with evidence of preoperative decompensation.

P-655 Live birth rate in the fresh cycle associated with number of oocytes in ovarian stimulation with individualised follitropin delta: an individual patient data meta-analysis

Abstract Study question What is the optimum number of oocytes retrieved to achieve a live birth for women undergoing ovarian stimulation with individualised follitropin delta? Summary answer The live birth rate (LBR) in the fresh cycle was highest in the range of 8-14 oocytes retrieved, peaking at 11 oocytes. What is known already The number of oocytes retrieved following ovarian stimulation for assisted reproductive technologies is regarded a prognostic marker of pregnancy outcome, where high numbers increase chances of live birth but also the risk of complications, especially ovarian hyperstimulation syndrome (OHSS). Thus, an optimum range of oocytes retrieved is essential. Still, there is no consensus regarding this range in fresh cycles. Optimum numbers between 6 and 15 oocytes have been suggested, taking the risk of OHSS into consideration. The individualised dosing algorithm for the recombinant follicle-stimulating hormone follitropin delta has a target range of 8–14 oocytes. Study design, size, duration Individual patient data meta-analysis of 1772 patients from 5 randomised controlled trials using individualised dosing of follitropin delta for ovarian stimulation, with fixed daily dosing based on serum anti-Müllerian hormone (AMH) and body weight. The analysis included patients with ≥1 oocyte retrieved. Outcomes of LBR and OHSS in the fresh stimulation cycle were evaluated in relation to number of oocytes retrieved. Subgroup analyses were performed based on age, AMH and number of oocytes retrieved. Participants/materials, setting, methods Participants were women, 18–42 years, undergoing first or second in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycle in a GnRH antagonist/long agonist protocol with human chorionic gonadotrophin or GnRH agonist triggering and IVF/ICSI. Single or double embryo/blastocyst transfer was performed on Day 3/5. All pregnancies were followed until birth. Predicted live birth was obtained using a logistic regression analysis with fractional polynomials to assess the association between number of oocytes retrieved and live birth. Main results and the role of chance The studied population (n = 1772) had a mean age of 32.6 years and median AMH of 17.7 pmol/l. Mean number of oocytes retrieved was 10.4, the LBR was 32.1% and the OHSS rate (any grade and onset) was 6.6%. The LBR steadily increased with the number of oocytes retrieved up to a plateau starting at 8 oocytes, with a LBR above 34% in the range of 8-14 oocytes retrieved, peaking at 34.9% for 11 oocytes. Beyond 14 oocytes, LBR gradually declined. By number of oocytes (grouped), the LBR was 27.8%, 33.6% and 30.9% at 1-7, 8-14 and ≥15 oocytes. In patients with embryo transfer, corresponding rates were 32.8%, 37.2% and 38.7%. In the subgroup analyses, LBR decreased with increasing age (32.7%, 30.7% and 23.4% at &amp;lt; 35, 35-37 and 38-42 years) while it was similar for AMH &amp;lt;15 and ≥15 pmol/l (30.4% and 31.3%, respectively). LBR was highest at 8-14 oocytes in patients &amp;lt;35 years (28.0%, 36.2% and 32.4% at 1-7, 8-14 and ≥15 oocytes), while it was consistently low (&amp;lt;26%) in patients 38-42 years, irrespective of number of oocytes retrieved. The OHSS rate (any grade) increased from 2.1% with 1-7 oocytes, to 5.2% with 8-14 oocytes and 17.0% with ≥15 oocytes. Limitations, reasons for caution A limitation of this study is the small number of patients with &amp;gt;20 oocytes retrieved in the studied population. Wider implications of the findings The current individual patient data meta-analysis suggests an optimum range of 8-14 oocytes retrieved to achieve a live birth in fresh cycles with follitropin delta. Furthermore, the analysis demonstrates a marked increase in OHSS rate from 15 oocytes retrieved. The results support the appropriateness of individualised follitropin delta dosing regimen. Trial registration number NCT01956110, NCT03228680, NCT03296527, NCT03564509, NCT03809429

Association of hyperuricemia with risk of cardiovascular disease according to the number of risk factors within target range

Background and aimsRisk factor modification may decrease the risk of cardiovascular disease (CVD). Whether risk factor modification can mitigate the effect of hyperuricemia on CVD is unclear. This study aimed to investigate the risk of CVD among individuals with hyperuricemia, according to risk factors on target, compared with controls without hyperuricemia. Methods and resultsThis prospective study included 91,722 participants free of CVD at baseline (2006–2007) of the Kailuan study. Individuals with hyperuricemia were categorized according to the number of seven selected risk factors within the guideline-recommended target range (nonsmoking, physical activity, healthy diet, guideline-recommended levels of body mass index, blood pressure, fasting blood glucose, and total cholesterol). During a median follow-up of 13.00 years, 671 out of 6740 individuals (9.96%) with hyperuricemia and 6301 out of 84,982 control subjects (7.41%) had incident CVD. Compared with control subjects without hyperuricemia, individuals with hyperuricemia who had 4 or 5 to 7 risk factors on target had no significant excess CVD risk, the hazard ratio (HR) (95% confidence internal [CI]) was 0.93 (0.79–1.10) and 0.88 (0.71–1.10), respectively. Among individuals with hyperuricemia, excess CVD risk decreased stepwise for a higher number of risk factors on target, the HR of CVD associated with per additional risk factor within target range was 0.82 (95% CI, 0.77–0.87). Similar results were yielded for CVD subtypes. ConclusionsAmong individuals with hyperuricemia, excess CVD risk decreased stepwise for a higher number of risk factors within target.

Radiating Encouragement: Further Investigation Into the Application of Gamma Ray Spectroscopy for Archaeological Prospection at the Roman Town of Silchester

ABSTRACTThis study builds on a preliminary investigation into the efficacy of gamma radiation surveying as a complementary tool for archaeological prospection. Improved surveying and data processing methods were implemented, including the use of a vehicle‐mounted Groundhog surveying system, use of alternative software tools and examination of the impacts of individual radionuclides. The study focuses on a range of targets within Insulae VII, XXXV and XXXIII in Silchester Roman town, Hampshire. Targets of interest included a polygonal temple, a house, ditches (including an Iron Age defensive ditch) and several Roman roads. While the survey revealed no measurable differences in the gamma radionuclide content of less substantial structures (such as the temple and house) and the surrounding soil, it successfully delineated major structures. The Roman roads, Iron Age defensive ditch and potentially an indication of a historic field boundary not present in modern records were clearly visible in the generated visualisations. The roads and field boundary appear as distinct linear features of depleted radioactivity. The location of the Iron Age ditch correlates with an area of elevated radioactivity. Notably, the technique not only successfully identified archaeological features but was also able to indicate differences in the properties of similar targets such as variations in road thickness. Further, the gamma radiation data indicates variations in the local geology attributable to historic changes in land use and geochemical composition. This latest study corroborates the findings of the preliminary investigation, demonstrating replicability, scalability and ability to enhance output data quality. Further research, including sampling and non‐destructive analysis of materials from the site, is needed to better explain observed results.

Design of a real-time frequency stabilization system for dual laser-based interferometer on EAST.

This study addresses the challenge of intermediate frequency (IF) instability in the far-infrared polarimeter/interferometer (POINT) of the Experimental Advanced Superconducting Tokamak (EAST) to ensure the accuracy and stability of electron density measurements. Sudden and extensive IF shifts of the lasers can cause instability and even measurement errors of the diagnostic system. This paper introduces a comprehensive solution for stabilizing IF fluctuations. First, analog IF is converted into digital form using an analog-to-digital converter, and the digitalized signal is processed by a digital signal system based on a ZYNQ processor. The exact value of the IF is obtained by acquiring the point of maximum amplitude through the fast Fourier transform method, while the ZYNQ processor loaded with a fuzzy control algorithm will precisely adjust the laser cavity length via piezoelectric ceramics, achieving frequency stabilization within a target range. Comparative analyses confirm the method's efficacy in managing sudden frequency shifts, maintaining stability within 850 ± 100kHz (a central frequency of 850kHz, fluctuating within a range of ±100kHz), with a control speed of 0.5s per action and robust against variations up to 270kHz. This efficient and rapid control mechanism fulfills the critical need for IF stabilization, ensuring the stability and precision of the POINT system in the EAST discharge experiments.

Role of Artificial Intelligence in Drug Discovery and Target Identification in Cancer.

Drug discovery and development (DDD) is a highly complex process that necessitates precise monitoring and extensive data analysis at each stage. Furthermore, the DDD process is both timeconsuming and costly. To tackle these concerns, artificial intelligence (AI) technology can be used, which facilitates rapid and precise analysis of extensive datasets within a limited timeframe. The pathophysiology of cancer disease is complicated and requires extensive research for novel drug discovery and development. The first stage in the process of drug discovery and development involves identifying targets. Cell structure and molecular functioning are complex due to the vast number of molecules that function constantly, performing various roles. Furthermore, scientists are continually discovering novel cellular mechanisms and molecules, expanding the range of potential targets. Accurately identifying the correct target is a crucial step in the preparation of a treatment strategy. Various forms of AI, such as machine learning, neural-based learning, deep learning, and network-based learning, are currently being utilised in applications, online services, and databases. These technologies facilitate the identification and validation of targets, ultimately contributing to the success of projects. This review focuses on the different types and subcategories of AI databases utilised in the field of drug discovery and target identification for cancer.

Pre-clinical Evidence-based Neuroprotective Potential of Naringin against Alzheimer's Disease-like Pathology: A Comprehensive Review.

Neurodegenerative disorders (NDs) are a group of progressive, chronic, and disabling disorders that are highly prevalent and the incidence is on a constant rise globally. Alzheimer's disease (AD), one of the most common neurodegenerative disorders is hallmarked by cognitive impairment, amyloid-β (Aβ) deposition, hyperphosphorylation of tau protein, cholinergic dysfunction, mitochondrial toxicity, and neurodegeneration. Available therapeutic agents only provide symptomatic relief and their use are limited due to serious side effects. Recent research has recognized flavonoids as potential multi-target biomolecules that can reduce the pathogenesis of AD. Naringin, a natural citrus flavonoid has been traditionally used to treat various NDs including AD, and has gained special attention because exhibits a neuroprotective effect by affecting numerous signaling pathways with minimum adverse effects. Naringin reduces deposition of Aβ, hyperphosphorylation of tau protein, cholinergic dysfunction, oxidative stress burden, mitochondrial toxicity, the activity of glutamate receptors, and apoptosis of the neuronal cells. Additionally, it reduces the expression of phosphorylated-P38/P38 and the NF-κB signaling pathway, showing that a wide range of molecular targets is involved in naringin's neuroprotective action. The present study describes the possible pharmacological targets, signaling pathways, and molecular mechanisms of naringin involved in neuroprotection against AD-like pathology. Based on the above pre-clinical reports it can be concluded that naringin could be an alternative therapeutic agent for the management of AD-like manifestation. Thus, there is a strong recommendation to perform more preclinical and clinical studies to develop naringin as a novel molecule that could be a multi-target drug to counteract AD.