Risk of new-onset diabetes and efficacy of pharmacological weight loss therapy.

AIMS: To develop a clinical risk model to identify individuals at higher risk of developing new-onset diabetes and who might benefit more from weight loss pharmacotherapy. MATERIALS AND METHODS: A total of 21 143 patients without type 2 diabetes at baseline from two TIMI clinical trials of stable cardiovascular patients were divided into a derivation (~2/3) and validation (~1/3) cohort. The primary outcome was new-onset diabetes. Twenty-seven candidate risk variables were considered, and variable selection was performed using multivariable Cox regression. The final model was evaluated for discrimination and calibration, and for its ability to identify patients who experienced a larger benefit from the weight loss medication lorcaserin in terms of risk of new-onset diabetes. RESULTS: During a median (interquartile range) follow-up of 2.3 (1.8-2.7) years, new-onset diabetes occurred in 1013 patients (7.7%). The final model included five independent predictors (glycated haemoglobin, fasting glucose, age, body mass index, and triglycerides/high-density lipoprotein). The clinical risk model showed good discrimination (Harrell's C-indices 0.802, 95% confidence interval [CI] 0.788-0.817 and 0.807, 95% CI 0.788-0.826) in the derivation and validation cohorts. The calibration plot demonstrated adequate calibration (2.5-year area under the curve was 81.2 [79.1-83.5]). While hazard ratios for new-onset diabetes with a weight-loss therapy were comparable across risk groups (annual risks of <1%, 1%-5%, and >5%), there was a sixfold gradient in absolute risk reduction from lowest to highest risk group (p = 0.027). CONCLUSIONS: The developed clinical risk model effectively predicts new-onset diabetes, with potential implications for personalized patient care and therapeutic decision making.

Design of Promising Thiazoloindazole-Based Acetylcholinesterase Inhibitors Guided by Molecular Docking and Experimental Insights.

Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer's disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 µM. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 ± 0.014 µM). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.

An organic-organometallic CO-releasing material comprising 4,4'-bipyridine and molybdenum subcarbonyl building blocks.

Over the past two decades, following the discovery of the important biological roles of carbon monoxide (CO), metal carbonyl complexes have been intensively studied as CO-releasing molecules (CORMs) for therapeutic applications. To improve the properties of "bare" low molecular weight CORMs, attention has been drawn to conjugating CORMs with macromolecular and inorganic scaffolds to produce CO-releasing materials (CORMAs) capable of storing and delivering large payloads of the gasotransmitter. A significant obstacle is to obtain CORMAs that retain the beneficial features of the parent CORMs. In the present work, a crystalline metal-organic framework (MOF) formulated as Mo(CO)3(4,4'-bipyridine)3/2 (Mobpy), with a structure based on Mo(CO)3 metallic nodes and bipyridine linkers, has been prepared in near quantitative yield by a straightforward reflux method, and found to exhibit CO-release properties that mimic those typically observed for molybdenum carbonyl CORMs. Mobpy was characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), FT-IR, FT-Raman and diffuse reflectance (DR) UV-vis spectroscopies, and 13C{1H} cross-polarization (CP) magic-angle spinning (MAS) NMR. The release of CO from Mobpy was studied by the deoxy-myoglobin (deoxy-Mb)/carbonmonoxy-myoglobin (MbCO) UV-vis assay. Mobpy liberates CO upon contact with a physiological buffer in the dark, leading to a maximum released amount of 1.3-1.5 mmol g-1, after 1.5 h at 37 °C, with half-lives of 0.5-1.0 h (time to transfer 0.5 equiv. of CO to Mb). In the solid-state and under open air, Mobpy undergoes complete decarbonylation over a period of 42 days, corresponding to a theoretical CO-release of 7.25 mmol g-1.

Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk.

BACKGROUND: Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering. METHODS: In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. RESULTS: A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups. CONCLUSIONS: In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.).

Maximum storage time of refrigerated blood and frozen plasma samples from tambaqui, Colossoma macropomum.

Blood analysis is an important tool for monitoring the health status of fish, but the time between collection and analysis can affect the outcome of the analysis. This study sought to determine the maximum time refrigerated blood and frozen plasma samples of the tambaqui, Colossoma macropomum, can be stored without affecting analysis. Samples from 12 fish were obtained, stored under refrigeration at 4 °C and evaluated after 0, 24, 48, 72, and 96 h, while samples from 14 fish were centrifuged, and the resulting plasma was frozen at -20 °C and then evaluated after 0, 8, 12, 16 and 20 weeks. The parameters analyzed were hematocrit (Ht), hemoglobin content (Hb), total erythrocytes (RBC), total (WBC) and differential leukocytes, total thrombocytes (TC), glucose content (Glc), total protein (TP), triglyceride content (TG), total cholesterol (CoT), and the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). For refrigerated whole blood samples, mean corpuscular hemoglobin content (MCHC) showed a transient decline in 24 h, and there were decreases in WBC, TC, Glc and TG that persisted until the 72 h sample point (for Glc and TG) or persisted until the 96 h sample point (for WBC and TC). A decrease in RBC was noted from 48 h on, while ALT was significantly higher in the 96 h sample. Significant decreases in lymphocytes, monocytes, neutrophils and eosinophils were noted from 48 h of storage on, while a significant decline in basophil counts were noted over the last two sampled timepoints. The coefficient of variation was greatest at the 96 h timepoint, indicating increased variability in measured parameters after 4 d of refrigeration. Plasma samples frozen at -20 °C showed a significant variation in ALT after 8 weeks, and increases in TP and TG after 20 weeks. Therefore, it is recommended that refrigerated tambaqui whole blood samples be analyzed within 24 h and frozen tambaqui plasma samples analyzed within 8 weeks.

Effect of seasonality and estuarine waters on the phytoplankton of the Guamá River (Belém, Amazon, Brazil).

This study aimed to analyze the application of the Phytoplankton Community Index-PCI and Functional Groups-FG in determining the water quality of the Guamá River (Pará, Amazônia, Brazil). Samplings occurred monthly for analyses of phytoplankton and physical and chemical parameters, for two years, at the station where water was collected for human supply consumption. Seasonality influenced electrical conductivity, total suspended solids, dissolved oxygen, transparency, winds, true color, and N-ammoniacal. The ebb tide showed high turbidity and suspended solids. The density varied seasonally with the highest values occurring in September and December (61.1 ind mL-1 and 60.2 ind mL-1, respectively). Chlorophyll-a was more elevated in December (21.0 ± 4.7 µg L-1) and chlorophyll-c higher in relation to clorophyll- b indicated the dominance of diatoms. Functional Group P prevailed in the study months. Through the PCI índex the waters of Guamá River varied from reasonable to excellent and the TSI ranged from oligo to mesotrophic. The use of Functional Groups proved to be a promising tool in the determination of water quality since it covered the most abundant species in the Environment, but the PCI is not adequate to characterize Amazonian white-waters rivers, which have diatoms as the leading dominant group.

Rhabdoviral Endogenous Sequences Identified in the Leishmaniasis Vector Lutzomyia longipalpis Are Widespread in Sandflies from South America.

Sandflies are known vectors of leishmaniasis. In the Old World, sandflies are also vectors of viruses while little is known about the capacity of New World insects to transmit viruses to humans. Here, we relate the identification of RNA sequences with homology to rhabdovirus nucleocapsids (NcPs) genes, initially in the Lutzomyia longipalpis LL5 cell lineage, named NcP1.1 and NcP2. The Rhabdoviridae family never retrotranscribes its RNA genome to DNA. The sequences here described were identified in cDNA and DNA from LL-5 cells and in adult insects indicating that they are transcribed endogenous viral elements (EVEs). The presence of NcP1.1 and NcP2 in the L. longipalpis genome was confirmed in silico. In addition to showing the genomic location of NcP1.1 and NcP2, we identified another rhabdoviral insertion named NcP1.2. Analysis of small RNA molecules derived from these sequences showed that NcP1.1 and NcP1.2 present a profile consistent with elements targeted by primary piRNAs, while NcP2 was restricted to the degradation profile. The presence of NcP1.1 and NcP2 was investigated in sandfly populations from South America and the Old World. These EVEs are shared by different sandfly populations in South America while none of the Old World species studied presented the insertions.

Mechanical Analysis of the Quasi-Static and Dynamic Composite Action in PV Modules with Viscoelastic Encapsulant.

The mechanical analysis of photovoltaics and building integrated photovoltaics is a key step for their optimal design and certification, and requires careful consideration, alongside solar power, durability and functionality issues. The solar cells are encapsulated in thin interlayers that are usually composed of a viscoelastic Ethylene-Vinyl Acetate compound, and protected by thin glass and/or plastic layers. This paper investigates the out-of-plane bending response of a full-scale commercial PV module and focuses attention on the shear bonding efficiency of the thin encapsulant for quasi-static and dynamic mechanical considerations. The parametric analytical analysis, carried out in this study for a laminated glass plate, highlights the possible consequences of the viscoelastic shear coupling on the cross-section load-bearing demand in the covers. As a direct effect of severe operational conditions (i.e., ageing, non-uniform/cyclic thermal gradients, humidity, extreme mechanical/thermal loads, etc.) the shear rigidity and adhesion of these films can suffer from repeated/progressive modification and even degradation, and thus induce major stress and deflection effects in the out-of-plane mechanical response of the PV module components. The minimum shear bond efficiency required to prevent mechanical issues is calculated for various configurations of technical interest. Accordingly, it is shown how the quasi-static and dynamic mechanical performance of the system modifies as a function of a more rigid or weak shear coupling.

SiaN-VO: Siamese Network for Visual Odometry.

Despite the significant advancements in drone sensory device reliability, data integrity from these devices remains critical in securing successful flight plans. A notable issue is the vulnerability of GNSS to jamming attacks or signal loss from satellites, potentially leading to incomplete drone flight plans. To address this, we introduce SiaN-VO, a Siamese neural network designed for visual odometry prediction in such challenging scenarios. Our preliminary studies have shown promising results, particularly for flights under static conditions (constant speed and altitude); while these findings are encouraging, they do not fully represent the complexities of real-world flight conditions. Therefore, in this paper, we have furthered our research to enhance SiaN-VO, improving data integration from multiple sensors and enabling more accurate displacement predictions in dynamic flight conditions, thereby marking a significant step forward in drone navigation technology.

Exploring the Luminescence, Redox, and Magnetic Properties in a Multivariate Metal-Organic Radical Framework.

Persistent neutral organic radicals are excellent building blocks for the design of functional molecular materials due to their unique electronic, magnetic, and optical properties. Among them, triphenylmethyl radical derivatives have attracted a lot of interest as luminescent doublet emitters. Although neutral organic radicals have been underexplored as linkers for building metal-organic frameworks (MOFs), they hold great potential as organic elements that could introduce additional electronic properties within these frameworks. Herein, we report the synthesis and characterization of a novel multicomponent metal-organic radical framework (PTMTCR@NR-Zn MORF), which is constructed from the combination of luminescent perchlorotriphenylmethyl tricarboxylic acid radical (PTMTCR) and nonemissive nonradical (PTMTCNR) organic linkers and Zn(II) ions. The PTMTCR@NR-Zn MORF structure is layered with microporous one-dimensional channels embedded within these layers. Kelvin probe force microscopy further confirmed the presence of both organic nonradical and radical linkers in the framework. The luminescence properties of the PTMTCR ligand (first studied in solution and in the solid state) were maintained in the radical-containing PTMTCR@NR-Zn MORF at room temperature as fluorescence solid-state quenching is suppressed thanks to the isolation of the luminescent radical linkers. In addition, magnetic and electrochemical properties were introduced to the framework due to the incorporation of the paramagnetic organic radical ligands. This work paves the way for the design of stimuli-responsive hybrid materials with tunable luminescence, electrochemical, and magnetic properties by the proper combination of closed- and open-shell organic linkers within the same framework.

Diastology in the intensive care unit: Challenges for the assessment and future directions.

Myocardial dysfunction is common in patients admitted to the intensive care unit (ICU). Septic disease frequently results in cardiac dysfunction, and sepsis represents the most common cause of admission and death in the ICU. The association between left ventricular (LV) systolic dysfunction and mortality is not clear for critically ill patients. Conversely, LV diastolic dysfunction (DD) seems increasingly recognized as a factor associated with poor outcomes, not only in sepsis but also more generally in critically ill patients. Despite recent attempts to simplify the diagnosis and grading of DD, this remains relatively complex, with the need to use several echocardiographic parameters. Furthermore, the current guidelines have several intrinsic limitations when applied to the ICU setting. In this manuscript, we discuss the challenges in DD classification when applied to critically ill patients, the importance of left atrial pressure estimates for the management of patients in ICU, and whether the study of cardiac dysfunction spectrum during critical illness may benefit from the integration of left ventricular and left atrial strain data to improve diagnostic accuracy and implications for the treatment and prognosis.

Synthesis of 6,8-diaminopurines via acid-induced cascade cyclization of 5-aminoimidazole precursors and preliminary anticancer evaluation.

Inspired by the pharmacological interest generated by 6-substituted purine roscovitine for cancer treatment, 5-aminoimidazole-4-carboxamidine precursors containing a cyanamide unit were prepared by condensation of 5-amino-N-cyanoimidazole-4-carbimidoyl cyanides with a wide range of primary amines. When these amidine precursors were combined with acids, a fast cascade cyclization occurred at room temperature, affording new 6,8-diaminopurines with the N-3 and N-6 substituents changed relatively to the original positions they occupied in the amidine and imidazole moieties of precursors. The efficacy and wide scope of this method was well demonstrated by an easy and affordable synthesis of 22 6,8-diaminopurines decorated with a wide diversity of substituents at the N-3 and N-6 positions of the purine ring. Preliminary in silico and in vitro assessments of these 22 compounds were carried out and the results showed that 13 of these tested compounds not only exhibited IC50 values between 1.4 and 7.5 µM against the colorectal cancer cell line HCT116 but also showed better binding energies than known inhibitors in docking studies with different cancer-related target proteins. In addition, good harmonization observed between in silico and in vitro results strengthens and validates this preliminary evaluation, suggesting that these novel entities are good candidates for further studies as new anticancer agents.

Body Composition, Coronary Microvascular Dysfunction, and Future Risk of Cardiovascular Events Including Heart Failure.

BACKGROUND: Body mass index (BMI) is a controversial marker of cardiovascular prognosis, especially in women. Coronary microvascular dysfunction (CMD) is prevalent in obese patients and a better discriminator of risk than BMI, but its association with body composition is unknown. OBJECTIVES: The authors used a deep learning model for body composition analysis to investigate the relationship between CMD, skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), and their contribution to adverse outcomes in patients referred for evaluation of coronary artery disease. METHODS: Consecutive patients (n = 400) with normal perfusion and preserved left ventricular ejection fraction on cardiac stress positron emission tomography were followed (median, 6.0 years) for major adverse events, including death and hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was quantified as stress/rest myocardial blood flow from positron emission tomography. SM, SAT, and VAT cross-sectional areas were extracted from abdominal computed tomography at the third lumbar vertebra using a validated automated algorithm. RESULTS: Median age was 63, 71% were female, 50% non-White, and 50% obese. Compared with the nonobese, patients with obesity (BMI: 30.0-68.4 kg/m2) had higher SAT, VAT, and SM, and lower CFR (all P < 0.001). In adjusted analyses, decreased SM but not increased SAT or VAT was significantly associated with CMD (CFR <2; OR: 1.38; 95% CI: 1.08-1.75 per -10 cm2/m2 SM index; P < 0.01). Both lower CFR and SM, but not higher SAT or VAT, were independently associated with adverse events (HR: 1.83; 95% CI: 1.25-2.68 per -1 U CFR and HR: 1.53; 95% CI: 1.20-1.96 per -10 cm2/m2 SM index, respectively; P < 0.002 for both), especially heart failure hospitalization (HR: 2.36; 95% CI: 1.31-4.24 per -1 U CFR and HR: 1.87; 95% CI: 1.30-2.69 per -10 cm2/m2 SM index; P < 0.004 for both). There was a significant interaction between CFR and SM (adjusted P = 0.026), such that patients with CMD and sarcopenia demonstrated the highest rate of adverse events, especially among young, female, and obese patients (all P < 0.005). CONCLUSIONS: In a predominantly female cohort of patients without flow-limiting coronary artery disease, deficient muscularity, not excess adiposity, was independently associated with CMD and future adverse outcomes, especially heart failure. In patients with suspected ischemia and no obstructive coronary artery disease, characterization of lean body mass and coronary microvascular function may help to distinguish obese phenotypes at risk for cardiovascular events.

Suspected tick-borne flavivirus meningoencephalomyelitis in dogs from the UK: six cases (2021).

OBJECTIVES: Tick-borne encephalitis virus and louping ill virus are neurotropic flaviviruses transmitted by ticks. Epidemiologically, tick-borne encephalitis is endemic in Europe whereas louping ill's predominant geographical distribution is the UK. Rarely, these flaviviruses affect dogs causing neurological signs. This case series aimed to describe the clinical, clinicopathological, and imaging findings, as well as the outcomes in six dogs with meningoencephalitis and/or meningomyelitis caused by a flavivirus in the UK in 2021. MATERIALS AND METHODS: Observational retrospective case-series study. Clinical data were retrieved from medical records of dogs with positive serological or immunohistochemical results from three different institutions from spring to winter 2021. RESULTS: Six dogs were included in the study. All dogs presented an initial phase of pyrexia and/or lethargy followed by progressive signs of spinal cord and/or intracranial disease. Magnetic resonance imaging showed bilateral and symmetrical lesions affecting the grey matter of the thalamus, pons, medulla oblongata, and thoracic or lumbar intumescences with none or mild parenchymal and meningeal contrast enhancement. Serology for tick-borne encephalitis virus was positive in five dogs with the presence of seroconversion in two dogs. The viral distinction between flaviviruses was not achieved. One dog with negative serology presented positive immunohistochemistry at post-mortem examination. Three dogs survived but presented neurological sequelae. Three dogs were euthanased due to the rapid progression of the clinical signs or static neurological signs. CLINICAL SIGNIFICANCE: These cases raise awareness of the presence of tick-borne encephalitis as an emergent disease or the increased prevalence of louping ill virus affecting dogs in the UK.

Comparative effectiveness and cost-effectiveness of cardioprotective glucose-lowering therapies for type 2 diabetes in Brazil: a Bayesian network model.

BACKGROUND: The escalating prevalence of type 2 diabetes (T2DM) poses an unparalleled economic catastrophe to developing countries. Cardiovascular diseases remain the primary source of costs among individuals with T2DM, incurring expenses for medications, hospitalizations, and surgical interventions. Compelling evidence suggests that the risk of cardiovascular outcomes can be reduced by three classes of glucose-lowering therapies (GLT), including SGLT2i, GLP-1A, and pioglitazone. However, an evidence-based and cost-effective protocol is still unavailable for many countries. The objective of the current study is to compare the effectiveness and cost-effectiveness of GLT in individuals with T2DM in Brazil. METHODS: We employed Bayesian Networks to calculate the incremental cost-effectiveness ratios (ICER), expressed in international dollars (Int$) per disease-adjusted life years [DALYs] averted. To determine the effectiveness of GLT, we conducted a systematic review with network meta-analysis (NMA) to provide insights for our model. Additionally, we obtained cardiovascular outcome incidence data from two real-world cohorts comprising 851 and 1337 patients in primary and secondary prevention, respectively. Our cost analysis took into account the perspective of the Brazilian public health system, and all values were converted to Int$. RESULTS: In the NMA, SGLT2i [HR: 0.81 (95% CI 0.69-0.96)], GLP-1A [HR: 0.79 (95% CI 0.67-0.94)], and pioglitazone [HR: 0.73 (95% CI 0.59-0.91)] demonstrated reduced relative risks of non-fatal cardiovascular events. In the context of primary prevention, pioglitazone yielded 0.2339 DALYs averted, with an ICER of Int$7,082 (95% CI 4,521-10,770) per DALY averted when compared to standard care. SGLT2i and GLP-1A also increased effectiveness, resulting in 0.261 and 0.259 DALYs averted, respectively, but with higher ICERs of Int$12,061 (95% CI: 7,227-18,121) and Int$29,119 (95% CI: 23,811-35,367) per DALY averted. In the secondary prevention scenario, all three classes of treatments were deemed cost-effective at a maximum willingness-to-pay threshold of Int$26,700. Notably, pioglitazone consistently exhibited the highest probability of being cost-effective in both scenarios. CONCLUSIONS: In Brazil, pioglitazone presented a higher probability of being cost-effective both in primary and secondary prevention, followed by SGLT2i and GLP-1A. Our findings support the use of cost-effectiveness models to build optimized and hierarchical therapeutic strategy in the management of T2DM. TRIAL REGISTRATION: CRD42020194415.

Integrating Fluorescent Nanodiamonds into Polymeric Microstructures Fabricated by Two-Photon Polymerization.

Nitrogen-vacancy (NV) and other color centers in diamond have attracted much attention as non-photobleaching quantum emitters and quantum sensors. Since microfabrication in bulk diamonds is technically difficult, embedding nanodiamonds with color centers into designed structures is a way to integrate these quantum emitters into photonic devices. In this study, we demonstrate a method to incorporate fluorescent nanodiamonds into engineered microstructures using two-photon polymerization (2PP). We studied the optimal concentration of nanodiamonds in the photoresist to achieve structures with at least one fluorescent NV center and good structural and optical quality. Fluorescence and Raman spectroscopy measurements were used to confirm the presence and location of the nanodiamonds, while absorbance measurements assessed scattering losses at higher concentrations. Our results show the feasibility of fabricating microstructures embedded within fluorescent nanodiamonds via 2PP for photonics and quantum technology applications.

Acclimatization of Sweet Potatoes Under in vitro Application of Diatomaceous Earth.

Diatomaceous earth is an organic naturally occurring material rich in silicon. This silicon source can be used in organic agriculture, it also has a great potential of use in the acclimatization of crops. However, there are no reports of the effects of diatomaceous earth supplementation on the micropropagation of sweet potato. Thus, the objective of this study was to evaluate the effects of different concentrations of diatomaceous earth applied in vitro on the growth, physiology and anatomy of sweet potato cv. 'Brazlândia Branca' after acclimatization. Four concentrations of diatomaceous earth. After 30 days of in vitro growth, the plants were transferred to a greenhouse for acclimatization. After 45 days, leaf number, shoot and root length, fresh and dry shoot and root mass, gas exchange, chlorophyll content, root and leaf anatomy. The experimental design was completely randomized. The supplementation of diatomaceous earth in the in vitro cultivation had beneficial effects, increasing the accumulation of mass, improving the photosynthetic apparatus and promoting favorable anatomical characteristics during the acclimatization of the sweet potato plants. In addition, the use of diatomaceous earth achieved adequate seedling development, with higher seedling quality and resistance to biotic and abiotic effects than attained with control treatment.

Risk Assessment of Kidney Disease Progression and Efficacy of SGLT2 Inhibition in Patients With Type 2 Diabetes.

OBJECTIVE: To develop a risk assessment tool to identify patients with type 2 diabetes (T2D) at higher risk for kidney disease progression and who might benefit more from sodium-glucose cotransporter 2 (SGLT2) inhibition. RESEARCH DESIGN AND METHODS: A total of 41,204 patients with T2D from four Thrombolysis In Myocardial Infarction (TIMI) clinical trials were divided into derivation (70%) and validation cohorts (30%). Candidate predictors of kidney disease progression (composite of sustained ≥40% decline in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney death) were selected with multivariable Cox regression. Efficacy of dapagliflozin was assessed by risk categories (low: <0.5%; intermediate: 0.5 to <2%; high: ≥2%) in Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58. RESULTS: There were 695 events over a median follow-up of 2.4 years. The final model comprised eight independent predictors of kidney disease progression: atherosclerotic cardiovascular disease, heart failure, systolic blood pressure, T2D duration, glycated hemoglobin, eGFR, urine albumin-to-creatinine ratio, and hemoglobin. The c-indices were 0.798 (95% CI, 0.774-0.821) and 0.798 (95% CI, 0.765-0.831) in the derivation and validation cohort, respectively. The calibration plot slope (deciles of predicted vs. observed risk) was 0.98 (95% CI, 0.93-1.04) in the validation cohort. Whereas relative risk reductions with dapagliflozin did not differ across risk categories, there was greater absolute risk reduction in patients with higher baseline risk, with a 3.5% absolute risk reduction in kidney disease progression at 4 years in the highest risk group (≥1%/year). Results were similar with the 2022 Chronic Kidney Disease Prognosis Consortium risk prediction model. CONCLUSIONS: Risk models for kidney disease progression can be applied in patients with T2D to stratify risk and identify those who experience a greater magnitude of benefit from SGLT2 inhibition.

Facile Access to Structurally Diverse Antimalarial Indoles Using a One-Pot A3 Coupling and Domino Cyclization Approach.

A multistep and diversity-oriented synthetic route aiming at the A3 coupling/domino cyclization of o-ethynyl anilines, aldehydes and s-amines is described. The preparation of the corresponding precursors included a series of transformations, such as haloperoxidation and Sonogashira cross-coupling reactions, amine protection, desilylation and amine reduction. Some products of the multicomponent reaction underwent further detosylation and Suzuki coupling. The resulting library of structurally diverse compounds was evaluated against blood and liver stage malaria parasites, which revealed a promising lead with sub-micromolar activity against intra-erythrocytic forms of Plasmodium falciparum. The results from this hit-to-lead optimization are hereby reported for the first time.

Assessment of Atherothrombotic Risk in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Risk of atherothrombotic events is not uniform in patients with type 2 diabetes mellitus (T2DM). Tailored risk assessment may help guide selection of pharmacotherapies for cardiovascular primary and secondary prevention. OBJECTIVES: The purpose of this study was to develop a risk model for atherothrombosis in patients with T2DM. METHODS: We developed and validated a risk model for myocardial infarction (MI) or ischemic stroke (IS) in a pooled cohort of 42,181 patients with T2DM from 4 TIMI (Thrombolysis In Myocardial Infarction) clinical trial cohorts. Candidate variables were assessed with multivariable Cox regression, and independent variables (P < 0.05) were retained in the final model. Discrimination and calibration were assessed. Treatment interactions with dapagliflozin (sodium-glucose cotransporter-2 inhibitor) and evolocumab (proprotein convertase subtilisin/kexin type 9 inhibitor) were explored in the DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis In Myocardial Infarction 58) and FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trials, respectively. RESULTS: Sixteen variables were independent predictors of MI or IS. The model identified a >8-fold gradient of MI or IS rates between the top vs bottom risk quintiles in the validation cohort (3-year Kaplan-Meier rate: 14.9% vs 1.4%; P < 0.0001). C-indexes were 0.704 and 0.706 in the derivation and validation cohorts, respectively. The model was well-calibrated in both primary and secondary prevention. Absolute reduction in the rates of MI or IS tended to be greater in patients with higher baseline predicted risk for both dapagliflozin (absolute risk reduction: 2.1% vs 0.2%) and evolocumab (absolute risk reduction: 3.2% vs 1.0%). CONCLUSIONS: We developed and validated a risk score for atherothrombotic events, leveraging 16 routinely assessed clinical variables in patients with T2DM. The score has the potential to improve risk assessment and inform clinical decision-making.