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Rui Juan Song, Guang Lin Zhang Department of Infectious Diseases, Anhui Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Hefei, People’s Republic of ChinaCorrespondence: Guang Lin Zhang, Department of Infectious Diseases, Anhui Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Hefei, People’s Republic of China, Email zhang_guang_lin@163.comBackground: Nocardiosis is primarily an opportunistic infection affecting immunocompromised individuals, with a predilection for the lungs, brain, or skin in those with compromised immune function. Granulomatous hepatitis caused by Nocardia is a rare clinical manifestation. This study aims to provide a systematic overview of the clinical features of Nocardiosis caused by Nocardia farcinica, enhancing our understanding of this disease.Methods: We report a case of a 75-year-old male with no underlying diseases presenting with a history of “recurrent fever for more than 4 months”, along with fatigue, poor appetite, and pleural and abdominal effusion. Despite treatment at multiple hospitals, the patient showed little improvement. Chest CT revealed chronic inflammation, small nodules, bilateral pleural effusion, and pleural thickening. Abdominal CT indicated multiple low-density lesions in the liver, multiple small calcifications, and abdominal effusion.Results: Liver biopsy suggested inflammatory changes, with focal granuloma formation. Metagenomic next-generation sequencing (mNGS) of liver tissue indicated Nocardia farcinica, leading to the final diagnosis of disseminated Nocardia farcinica granulomatous hepatitis.Conclusion: Nocardia infection is a rare disease primarily observed in immunocompromised patients but can also occur in those with normal immune function. The clinical and radiological features lack specificity; however, the utilization of mNGS technology enables rapid identification of the pathogenic microorganism. Nocardia farcinica is generally susceptible to sulfonamide drugs and amikacin, offering viable treatment options.Keywords: nocardia farcinica, granulomatous hepatitis, disseminated infection, mNGS Technology, TMP-SMX

Qing-Liang Fang,1,* Kai-Chun Li,2,* Lei Wang,1 Xiang-Lian Gu,1 Ren-Jie Song,1 Song Lu1 1Department of Radiation Oncology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Department of Oncology, Tianyou Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing-Liang FangDepartment of Radiation Oncology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaTel +8621-64385700Email yuxun9582581581@163.comObjective: This study set out to explore the regulatory mechanism of miR-130a-5p in cisplatin (DDP)-resistant gastric cancer (GC) cells.Materials and Methods: Forty cases of GC and paracancerous tissues were collected, and the miR-130a-5p and CCL22 levels were detected by qRT-PCR. DDP-resistant cell lines of GC cells were established. Cell viability, invasion, and apoptosis were measured by CCK-8, Transwell, and flow cytometry, respectively. The relationship between miR-130a-5p and CCL22 was verified by dual-luciferase reporter enzyme, and the protein levels of caspase-3, bax, bcl-2, and CCL22 were determined by Western blot.Results: miR-130a-5p was low expressed in GC tissues and cells, while CCL22 showed marked negative correlation, and the area under the curve (AUC) for diagnosing GC was not less than 0.850. Up-regulating miR-130a-5p or knocking down CCL22 expression can inhibit the proliferation and invasion of GC cells and promote their apoptosis, reverse the resistance of NCI-N87/DDP to DDP, and also enhance the chemosensitivity of GC cells. Dual-luciferase reporter enzyme identified that there was a targeted relationship between miR-130a-5p and CCL22. At the same time, miR-130a-5p and CCL22 were up-regulated or down-regulated, and the malignant proliferation, invasion, apoptosis, and DDP chemotherapy resistance of the cells had no difference compared with miR-NC with transfection-unrelated sequences.Conclusion: Up-regulating miR-130a-5p can enhance the sensitivity of DDP-resistant GC cells to chemotherapy and regulate their biological function by targeted inhibition of CCL22.Keywords: miR-130a-5p, CCL22, cisplatin, gastric cancer, chemosensitivity

Tasnim F Imran,1–3,* Daniel Posner,1,4,* Jacqueline Honerlaw,1 Jason L Vassy,1,2 Rebecca J Song,1 Yuk-Lam Ho,1 Steven J Kittner,5 Katherine P Liao,1,2 Tianxi Cai,1,6 Christopher J O’Donnell,1,2 Luc Djousse,1,2 David R Gagnon,1,4 J Michael Gaziano,1,2 Peter WF Wilson,7,8 Kelly Cho1,2 On behalf of the VA Million Veteran Program 1Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA; 2Department of Medicine, Division of Aging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 3Department of Medicine, Cardiology Section, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA; 4Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; 5Department of Neurology, Baltimore VA Medical Center and University of Maryland School of Medicine, Baltimore, MD, USA; 6Harvard T. H. Chan School of Public Health, Boston, MA, USA; 7Atlanta VA Medical Center, Decatur, GA, USA; 8Department of Medicine, Division of Cardiovascular Disease, Emory University School of Medicine, Atlanta, GA, USA *These authors contributed equally to this work Background: Large databases provide an efficient way to analyze patient data. A challenge with these databases is the inconsistency of ICD codes and a potential for inaccurate ascertainment of cases. The purpose of this study was to develop and validate a reliable protocol to identify cases of acute ischemic stroke (AIS) from a large national database.Methods: Using the national Veterans Affairs electronic health-record system, Center for Medicare and Medicaid Services, and National Death Index data, we developed an algorithm to identify cases of AIS. Using a combination of inpatient and outpatient ICD9 codes, we selected cases of AIS and controls from 1992 to 2014. Diagnoses determined after medical-chart review were considered the gold standard. We used a machine-learning algorithm and a neural network approach to identify AIS from ICD9 codes and electronic health-record information and compared it with a previous rule-based stroke-classification algorithm.Results: We reviewed administrative hospital data, ICD9 codes, and medical records of 268 patients in detail. Compared with the gold standard, this AIS algorithm had a sensitivity of 91%, specificity of 95%, and positive predictive value of 88%. A total of 80,508 highly likely cases of AIS were identified using the algorithm in the Veterans Affairs national cardiovascular disease-risk cohort (n=2,114,458).Conclusion: Our algorithm had high specificity for identifying AIS in a nationwide electronic health-record system. This approach may be utilized in other electronic health databases to accurately identify patients with AIS. Keywords: acute ischemic stroke, algorithm, large databases, big data, administrative health data, cerebrovascular accident

Carboazidation and diazidation were carried out on 1,3-diene compounds using TMSN 3 as the azide source and MeCN as the cyanoalkylation reagent. This method exhibits excellent functional group tolerance, a broad substrate range, and a short reaction time, providing an effective pathway for synthesizing valuable azides. Our report introduces an unprecedented strategy for the carboazidation and diazidation of 1,3-dienes, with mechanism studies indicating that the reaction involves a radical pathway.

Organosilicon compounds have attracted considerable attention because of their special biological activities. Direct difunctionalization of unsaturated hydrocarbons with organosilicon reagents for the efficient construction of synthetically valuable silicon-functionalized compounds are featured with a high step and atom economy, which could form carbon-silicon/carbon-carbon bonds or carbon-silicon/carbon-hetero bonds in one step. This review summarizes the recent advances on this topic based on different unsaturated hydrocarbons along with typical examples and mechanisms.

Purpose: Traumatic brain injury (TBI), currently a major global public health problem, imposes a significant economic burden on society and families. We aimed to quantify and predict the incidence and severity of TBI by analyzing its incidence, prevalence, and years lived with disability (YLDs). The epidemiological changes in TBI from 1990 to 2019 were described and updated to provide a reference for developing prevention, treatment, and incidence-reducing measures for TBI., Methods: A secondary analysis was performed on the incidence, prevalence, and YLDs of TBI by sex, age group, and region (n = 21,204 countries and territories) between 1990 and 2019 using the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Proportions in the age-standardized incidence rate due to underlying causes of TBI and proportions of minor and moderate or severe TBI were also reported., Results: In 2019, there were 27.16 million (95% uncertainty intervals (UI): 23.36 - 31.42) new cases of TBI worldwide, with age-standardized incidence and prevalence rates of 346 per 100,000 population (95% UI: 298 - 401) and 599 per 100,000 population (95% UI: 573 - 627), respectively. From 1990 to 2019, there were no significant trends in global age-standardized incidence (estimated annual percentage changes: -0.11%, 95% UI: -0.18% - -0.04%) or prevalence (estimated annual percentage changes: 0.01%, 95% UI: -0.04% - 0.06%). TBI caused 7.08 million (95% UI: 5.00 - 9.59) YLDs in 2019, with age-standardized rates of 86.5 per 100,000 population (95% UI: 61.1 - 117.2). In 2019, the countries with higher incidence rates were mainly distributed in Central Europe, Eastern Europe, and Australia. The 2019 global age-standardized incidence rate was higher in males than in females. The 2019 global incidence of moderate and severe TBI was 182.7 per 100,000 population, accounting for 52.8% of all TBI, with falls and road traffic injuries being the main causes in most regions., Conclusions: The incidence of moderate and severe TBI was slightly higher in 2019, and TBI still accounts for a significant portion of the global injury burden. The likelihood of moderate to severe TBI and the trend of major injury under each injury cause from 1990 to 2019 and the characteristics of injury mechanisms in each age group are presented, providing a basis for further research on injury causes in each age group and the future establishment of corresponding policies and protective measures., (Copyright © 2024 Chinese Medical Association. Published by Elsevier B.V. All rights reserved.)

It is still a challenge to construct single-atom level reduction and oxidation sites in single-component photocatalyst by manipulating coordination configuration for photocatalytic water splitting. Herein, the atomically dispersed asymmetric configuration of six-coordinated Co-S 2 O 4 (two exposed S atoms, two OH groups, and two Co─O─Zn bonds) suspending on ZnIn 2 S 4 nanosheets verified by combining experimental analysis with theoretical calculation, is applied into photocatalytic water splitting. The Co-S 2 O 4 site immobilized by Vs acts as oxidation sites to guide electrons transferring to neighboring independent S atom, achieving efficient separation of reduction and oxidation sites. It is worth mentioning that stabilized Co-S 2 O 4 configuration show dynamic structure evolution to highly active Co-S 1 O 4 configuration (one exposed S atom, one OH group, and three Co─O─Zn bonds) in reaction, which lowers energy barrier of transition state for H 2 O activization. Ultimately, the optimized photocatalyst exhibits excellent photocatalytic activity for water splitting (H 2 : 80.13 µmol g -1 h -1 , O 2 : 37.81 µmol g -1 h -1 ) and outstanding stability than that of multicomponent photocatalysts due to dynamic and reversible evolution between stable Co-S 2 O 4 configuration and active Co-S 1 O 4 configuration. This work demonstrates new cognitions on immobilized strategy through vacancy inducing, manipulating coordination configuration, and dynamic evolution mechanism of single-atom level catalytic site in photocatalytic water splitting., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Heart rate, a measure of the frequency of the cardiac cycle, reflects the health of the cardiovascular system, metabolic rate, and activity of the autonomic nervous system. Whether changes in resting heart rate are related to lifespan has not yet been explored to our best knowledge. In this study, we examined the association between resting heart rate and lifespan using linear regression in the Paris Prospective Study I, the Whitehall I Study, and the Framingham Heart Study. We used Cox proportional hazards regression to relate changes in heart rate over years to mortality risk. We observed a statistically significant association between increases in resting heart rate over a 5-year period and risk of mortality in the Paris Prospective Study I (HR mortality per 10 bpm increase over time: 1.20; 95% CI: 1.13 to 1.27) and over an 8-year period in the Framingham Heart Study (HR: 1.13; 95% CI: 1.07 to 1.19 for men and HR: 1.09; 95% CI: 1.04 to 1.15 for women), after adjusting for classical risk factors and resting heart rate. Our study shows that men and women who increase their resting heart rate over time increase their risk of mortality., (© 2024. The Author(s).)

This study elucidates the mechanisms and principles governing chemoselectivity in synthesizing two distinct N-heterocycles, benzimidazole thiazine and benzothiazole imidazole, through BF 3 •OEt 2 -catalyzed cyclization reactions of propargyl alcohols with benzimidazole thiols. Employing density functional theory calculations, we highlight the crucial role of fluorine source in influencing chemoselectivity. In DCM, BF 3 , as the catalytic center, coordinates with propargyl alcohol's hydroxyl group to form a precursor. Conversely, in DMF, [BF 2 •DMF] + , formed from DMF and BF 3 •OEt 2 , acts as the catalytic center, activating the propargyl alcohol's hydroxyl group. The mechanisms in both solvents involve sequential steps: B-O bond formation, C-O bond cleavage, S-C bond formation, hydrogen atom transfer (HAT), cyclization, and deprotonation. A notable difference is the HAT process: in DCM, it follows a 1,5-HAT process, while in DMF, BF 4 - formation from DMF and BF 3 •OEt 2 provides a fluorine source and introduces steric hindrance, favoring a 1,6-HAT process and leading to unique chemoselectivity. This pioneering research showcases the impact of DMF on cyclization reactions, offering valuable insights for comprehending and designing reactions driven by fluorine sources. Crucially, our results propose an innovative reaction mechanism featuring lower potential energy surfaces, enhancing our understanding of the intricate interplay among reactants, catalysts, and solvents.

1,4-dioxane is a potential carcinogen in water and is difficult to deal with due to its robust cycloether bond and complete miscibility with water. To remove 1,4-dioxane in an economically viable and environmentally friendly way, a series of carbon aerogels were synthesized as adsorbents for 1,4-dioxane. The experiment results showed that adsorption performances were closely related to the preparation conditions of carbon aerogels, such as the molar ratio, heating rate, pyrolysis temperature and residence time, which were carefully controlled. Scanning electron microscope analysis revealed the presence of a three-dimensional porous network structure in carbon aerogels. Brunauer-Emmett-Teller analysis results demonstrated an increase in specific surface area (673.89 m 2 /g) and total pore volume after carbonization, with an increase in mesoporous porosity and a decrease in microporosity. When considering each variable individually, the highest specific surface area of prepared carbon aerogels was achieved at a pyrolysis temperature of 800 °C, a holding time of 1 h, and a heating rate of 2 °C/min. Under optimal experimental conditions, the adsorption removal of 1,4-dioxane by carbon aerogels exceeded 95%, following quasi-second-order kinetics and Langmuir isothermal adsorption isotherms, indicating that monolayer adsorption on the surface of carbon aerogels occurred. The maximum adsorption capacity obtained was 67.28 mg/g at a temperature of 318 K, which was attributed to the presence of a large proportion of mesopores and abundant micropores simultaneously in carbon aerogels. Furthermore, with the interference of chlorinated solvents such as trichloroethylene (TCE), the removal efficiency of 1,4-dioxane had no obvious inhibition effect. Regeneration experiments showed that after five continuous cycles, the carbon aerogels still kept a comparable adsorption capacity, which illustrates its potential application in 1,4-dioxane-polluted water purification.

Here, an Ir/Zn-cocatalyzed atroposelective [2+2+2] cycloaddition of 1,6-diynes and ynamines was developed, forging various functionalized C─N axially chiral indoles and pyrroles in generally good to excellent yields (up to 99%), excellent chemoselectivities, and high enantioselectivities (up to 98% enantiomeric excess) with wide substrate scope. This cocatalyzed strategy not only provided an alternative promising and reliable way for asymmetric alkyne [2+2+2] cyclotrimerization in an easy handle but also settled the issues of previous [Rh(COD) 2 ]BF 4 -catalyzed system on the construction of C─N axial chirality such as complex operations, limited substrate scope, and low efficiency. In addition, control experiments and theoretical calculations disclosed that Zn(OTf) 2 markedly reduced the barrier of migration insertion to significantly increase reaction efficiency, which was distinctly different from previous work on the Lewis acid for improving reaction yield through accelerating oxidative addition and reductive elimination.

Background: There is inconsistent evidence on the association of moderate alcohol consumption and stroke risk in the general population and is not well studied among U.S. Veterans. Furthermore, it is unclear whether primarily drinking beer, wine, or liquor is associated with a difference in stroke risk., Methods: The study included 185,323 Million Veteran Program participants who self-reported alcohol consumption on the Lifestyle Survey. Moderate consumption was defined as 1-2 drinks/day and beverage preference of beer, wine or liquor was defined if ≥ 50% of total drinks consumed were from a single type of beverage. Strokes were defined using ICD-9 and ICD-10 codes from the participants' electronic health record., Results: The mean (sd) age of the sample was 64 (13) years and 11% were women. We observed 4,339 (94% ischemic; 6% hemorrhagic) strokes over a median follow-up of 5.2 years. In Cox models adjusted for age, sex, race, education, income, body mass index, smoking, exercise, diet, cholesterol, prevalent diabetes, prevalent hypertension, lipid-lowering medication, antihypertensive medication, and diabetes medication, moderate alcohol consumption (1-2 drinks/day) was associated with a 22% lower risk of total stroke compared with never drinking [Hazards ratio (HR) 95% confidence interval (CI): 0.78 (0.67, 0.92)]. When stratifying by stroke type, we observed a similar protective association with moderate consumption and ischemic stroke [HR (95% CI): 0.76 (0.65, 0.90)], but a non-statistically significant higher risk of hemorrhagic stroke [HR (95% CI): 1.29 (0.64, 2.61)]. We did not observe a difference in ischemic or hemorrhagic stroke risk among those who preferred beer, liquor or wine vs. no beverage preference. When stratifying by prior number of hospital visits (≤ 15, 16-33, 34-64, ≥ 65) as a proxy for health status, we observed attenuation of the protective association with greater number of visits [HR (95% CI): 0.87 (0.63, 1.19) for ≥ 65 visits vs. 0.80 (0.59, 1.08) for ≤ 15 visits]., Conclusions: We observed a lower risk of ischemic stroke, but not hemorrhagic stroke with moderate alcohol consumption and did not observe substantial differences in risk by beverage preference among a sample of U.S. Veterans. Healthy user bias of moderate alcohol consumption may be driving some of the observed protective association., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: A healthful plant-based diet was associated with lower risks of coronary heart disease and type 2 diabetes, and a favourable profile of adiposity-associated biomarkers, while an unhealthful plant-based diet was associated with elevated risk of cardiometabolic disease in health professional populations. However, little is known about the associations between plant-based dietary patterns and risk of cardiovascular disease (CVD) in US veterans., Methods: The study population consisted of 148 506 participants who were free of diabetes, CVD and cancer at baseline in the Veterans Affairs (VA) Million Veteran Program. Diet was assessed using a Food Frequency Questionnaire at baseline. We calculated an overall Plant-Based Diet Index (PDI), a healthful PDI (hPDI) and an unhealthful PDI (uPDI). The CVD endpoints included non-fatal myocardial infarction (MI) and acute ischaemic stroke (AIS) identified through high-throughput phenotyping algorithms approach and fatal CVD events identified by searching the National Death Index., Results: With up to 8 years of follow-up, we documented 5025 CVD cases. After adjustment for confounding factors, a higher PDI was significantly associated with a lower risk of CVD (HR comparing extreme quintiles=0.75, 95% CI 0.68 to 0.82, P trend <0.0001). We observed an inverse association between hPDI and the risk of CVD (HR comparing extreme quintiles=0.71, 95% CI 0.64 to 0.78, P trend <0.001), whereas uPDI was positively associated with the risk of CVD (HR comparing extreme quintiles=1.12, 95% CI 1.02 to 1.24, P trend <0.001). We found similar associations of hPDI with subtypes of CVD; a 10-unit increment in hPDI was associated with HRs (95% CI) of 0.81 (0.75 to 0.87) for fatal CVD, 0.86 (0.79 to 0.94) for non-fatal MI and 0.86 (0.78 to 0.95) for non-fatal AIS., Conclusions: Plant-based dietary pattern enriched with healthier plant foods was associated with a substantially lower CVD risk in US veterans., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background The lipid hypothesis postulates that lower blood cholesterol is associated with reduced coronary heart disease (CHD) risk, which has been challenged by reports of a U-shaped relation between cholesterol and death in recent studies. We sought to examine whether the U-shaped relationship is true and to assess the impact of age on this association. Method and Results We conducted a prospective cohort study of 4 467 942 veterans aged >18 years, with baseline outpatient visits from 2002 to 2007 and follow-up to December 30, 2018, in the Veterans Health Administration electronic health record system. We observed a J-shaped relation between total cholesterol (TC) and CHD mortality after a comprehensive adjustment of confounding factors: flat for TC <180 mg/dL, and greater risk was present at higher cholesterol levels. Compared with veterans with TC between 180 and 199 mg/dL, the multiadjusted hazard ratios (HRs) for CHD death were 1.03 (95% CI, 1.02-1.04), 1.07 (95% CI, 1.06-1.09), 1.15 (95% CI, 1.13-1.18), 1.25 (95% CI, 1.22-1.28), and 1.45 (95% CI, 1.42-1.49) times greater among veterans with TC (mg/dL) of 200 to 219, 220 to 239, 140 to 259, 260 to 279 and ≥280, respectively. Similar J-shaped TC-CHD mortality patterns were observed among veterans with and without statin use at or before baseline. Conclusions The cholesterol paradox, for example, higher CHD death in patients with a low cholesterol level, was a reflection of reverse causality, especially among older participants. Our results support the lipid hypothesis that lower blood cholesterol is associated with reduced CHD. Furthermore, the hypothesis remained true when TC was low due to use of statins or other lipid-lowering medication.

Purpose: The aim of this study was to understand the serum metabolomic signatures of moderate-to-vigorous physical activity (MVPA) and sedentary behavior, and further associate their metabolomic signatures with incident cardiometabolic diseases., Methods: This analysis included 2711 US Hispanics/Latinos from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 yr (2008-2011). An untargeted, liquid chromatography-mass spectrometry was used to profile the serum metabolome. The associations of metabolites with accelerometer-measured MVPA and sedentary time were examined using survey linear regressions adjusting for covariates. The weighted correlation network analysis identified modules of correlated metabolites in relation to sedentary time, and the modules were associated with incident diabetes, dyslipidemia, and hypertension over the 6-yr follow-up., Results: Of 624 metabolites, 5 and 102 were associated with MVPA and sedentary behavior at false discovery rate (FDR) <0.05, respectively, after adjusting for socioeconomic and lifestyle factors. The weighted correlation network analysis identified 8 modules from 102 metabolites associated with sedentary time. Four modules (branched-chain amino acids, erythritol, polyunsaturated fatty acid, creatine) were positively, and the other four (acyl choline, plasmalogen glycerol phosphatidyl choline, plasmalogen glycerol phosphatidyl ethanolamine, urea cycle) were negatively correlated with sedentary time. Among these modules, a higher branched-chain amino acid score and a lower plasmalogen glycerol phosphatidyl choline score were associated with increased risks of diabetes and dyslipidemia. A higher erythritol score was associated with an increased risk of diabetes, and a lower acyl choline score was linked to an increased risk of hypertension., Conclusions: In this study of US Hispanics/Latinos, we identified multiple serum metabolomic signatures of sedentary behavior and their associations with risk of incident diabetes, hypertension, and dyslipidemia. These findings suggest a potential role of circulating metabolites in the links between sedentary behavior and cardiometabolic diseases., (Copyright © 2023 by the American College of Sports Medicine.)

Objectives: This study evaluated the ability of a preoperative contrast-enhanced CT (CECT)-based radiomics nomogram to differentiate benign and malignant primary retroperitoneal tumors (PRT)., Methods: Images and data from 340 patients with pathologically confirmed PRT were randomly placed into training (n = 239) and validation sets (n = 101). Two radiologists independently analyzed all CT images and made measurements. Key characteristics were identified through least absolute shrinkage selection combined with four machine-learning classifiers (support vector machine, generalized linear model, random forest, and artificial neural network back propagation) to create a radiomics signature. Demographic data and CECT characteristics were analyzed to formulate a clinico-radiological model. Independent clinical variables were merged with the best-performing radiomics signature to develop a radiomics nomogram. The discrimination capacity and clinical value of three models were quantified by the area under the receiver operating characteristics (AUC), accuracy, and decision curve analysis., Results: The radiomics nomogram was able to consistently differentiate between benign and malignant PRT in the training and validation datasets, with AUCs of 0.923 and 0.907, respectively. Decision curve analysis manifested that the nomogram achieved higher clinical net benefits than did separate use of the radiomics signature and clinico-radiological model., Conclusions: The preoperative nomogram is valuable for differentiating between benign and malignant PRT; it can also aid in treatment planning., Key Points: • A noninvasive and accurate preoperative determination of benign and malignant PRT is crucial to identifying suitable treatments and predicting disease prognosis. • Associating the radiomics signature with clinical factors facilitates differentiation of malignant from benign PRT with improved diagnostic efficacy (AUC) and accuracy from 0.772 to 0.907 and from 0.723 to 0.842, respectively, compared with the clinico-radiological model alone. • For some PRT with anatomically special locations and when biopsy is extremely difficult and risky, a radiomics nomogram may provide a promising preoperative alternative for distinguishing benignity and malignancy., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Physical activity promotes health and is particularly important during middle and older age for decreasing morbidity and mortality. We assessed the correlates of changes over time in moderate-to-vigorous physical activity (MVPA) in Hispanic/Latino adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL: mean [SD] age 49.2 y [11.5]) and compared them to a cohort of primarily White adults from the Framingham Heart Study (FHS: mean [SD] 46.9 y [9.2])., Methods: Between 2008 and 2019, we assessed accelerometry-based MVPA at two time points with an average follow-up of: 7.6 y, SD 1.3 for HCHS/SOL, and 7.8 y, SD 0.7 for FHS. We used multinomial logistic regression to relate socio-demographic and health behaviors with changes in compliance with 2018 US recommendations for MVPA from time 1 to time 2 (remained active or inactive; became active or inactive) across the two cohorts., Results: In HCHS/SOL mean MVPA was 22.6 (SD, 23.8) minutes at time 1 and dropped to 16.7 (19.0) minutes at time 2. In FHS Mean MVPA was 21.7 min (SD, 17.7) at time 1 and dropped to 21.3 min (SD, 19.2) at time 2. Across both cohorts, odds of meeting MVPA guidelines over time were about 6% lower in individuals who had lower quality diets vs. higher, about half in older vs. younger adults, about three times lower in women vs. men, and 9% lower in individuals who had a higher vs. lower BMI at baseline. Cohorts differed in how age, gender, income, education, depressive symptoms, marital status and perception of general health and pain associated with changes in physical activity. High income older Hispanics/Latino adults were more likely to become inactive at the follow-up visit as were HCHS/SOL women who were retired and FHS participants who had lower levels of education and income. Higher depressive symptomology was associated with becoming active only in HCHS/SOL women. Being male and married was associated with becoming inactive in both cohorts. Higher perception of general health and lower perception of pain were associated with remaining active only in FHS adults., Conclusions: These findings highlight potentially high-risk groups for targeted MVPA intervention., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Mitochondria, the energy factories of higher eukaryotes, provide energy (ATP) for life activities through aerobic respiration. They possess their own genome, mitochondrial DNA (mtDNA), which encodes 37 genes. Mutations in mtDNA cause mitochondrial diseases, and more than 100 pathogenic mutations have been identified in human mtDNA, with a total incidence rate of about 1/5000. In recent years, advances in CRISPR-based base editing technology have enabled accurate editing of nuclear genes. However, it remains a challenge to achieve precise base editing on mtDNA due to the difficulty of guide RNA in the CRISPR system passing through the mitochondrial double-membrane. In 2020, David R. Liu's group at Harvard University reported a double-stranded DNA deaminase DddA from Burkholderia cenocepacia , which was fused with the programmable transcription activator-like effector (TALE) and uracil glycosylase inhibitor (UGI) to develop DddA-derived cytosine base editors (DdCBEs). Using DdCBEs, they were able to achieve specific and efficient C?G to T?A conversion on mtDNA for the first time. In this review, we summarize the recent progress of mitochondrial base editing technology based on DddA and prospect its future application prospects. The information presented may facilitate interested researchers to grasp the principles of mitochondrial base editing, to use relevant base editors in their own studies, or to optimize mitochondrial base editors in the future.

Objective: To examine the association between adherence to plant-based diets and mortality., Design: Prospective study. We calculated a plant-based diet index (PDI) by assigning positive scores to plant foods and reverse scores to animal foods. We also created a healthful PDI (hPDI) and an unhealthful PDI (uPDI) by further separating the healthy plant foods from less-healthy plant foods., Setting: The VA Million Veteran Program., Participants: 315 919 men and women aged 19-104 years who completed a FFQ at the baseline., Results: We documented 31 136 deaths during the follow-up. A higher PDI was significantly associated with lower total mortality (hazard ratio (HR) comparing extreme deciles = 0·75, 95 % CI: 0·71, 0·79, P trend < 0·001]. We observed an inverse association between hPDI and total mortality (HR comparing extreme deciles = 0·64, 95 % CI: 0·61, 0·68, P trend < 0·001), whereas uPDI was positively associated with total mortality (HR comparing extreme deciles = 1·41, 95 % CI: 1·33, 1·49, P trend < 0·001). Similar significant associations of PDI, hPDI and uPDI were also observed for CVD and cancer mortality. The associations between the PDI and total mortality were consistent among African and European American participants, and participants free from CVD and cancer and those who were diagnosed with major chronic disease at baseline., Conclusions: A greater adherence to a plant-based diet was associated with substantially lower total mortality in this large population of veterans. These findings support recommending plant-rich dietary patterns for the prevention of major chronic diseases.

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.

Background Premature onset of cardiovascular disease (CVD) imposes a significant societal burden and challenges prevention efforts. Methods and Results Trends in the incidence of premature CVD (before age 55, 60, or 65 years, separate analysis for each threshold) were evaluated in 14 464 Framingham Heart Study participants over 7 decades of observation (1950-2019). The change in the incidence of premature CVD (per decade) in men and women was assessed using overdispersed Poisson regression (accounting for cohort effects), adjusting for age at entry and age at onset of premature CVD within each decade. CVD was defined as a composite of fatal or nonfatal coronary heart disease, stroke or transient ischemic attack, peripheral vascular disease, and heart failure. There were 2223 first CVD events (832 in women) before age 65 years during 282 481 person-years of observations (154 587 in women) between 1950 and 2019. The age-adjusted CVD incidence before age 65 years decreased from 14.8 per 1000 person-years (1950-1959) to 4.69 per 1000 person-years (2010-2019) in men and from 7.23 per 1000 person-years (1950-1959) to 1.73 per 1000 person-years (2010-2019) in women. In adjusted analyses, the incidence of premature CVD decreased per decade in men (18.4% [95% CI, 12.0%-24.0%], for onset before age 55 years; 19.5% [95% CI, 12.0%-27.0%], for onset before age 60 years; 21.3% [95% CI, 16.0%-27.0%], for onset before age 65 years) and women (15.1% [95% CI, 7.0%-22.0%], for onset before age 55 years; 14.0% [95% CI, 6.0%-22.0%], for onset before age 60 years; 18.2% [95% CI, 12.0%-24.0%], for onset before age 65 years). The decline in premature CVD was accompanied by a reduction in smoking and increased use of lipid-lowering treatments across the decades. Incidence of premature coronary heart disease decreased, whereas the contribution of stroke to premature CVD burden increased over time. Conclusions The incidence of premature CVD has decreased among White adults in the Framingham cohort over the past 70 years; the residual burden of premature stroke warrants further study. Additional studies of trends in premature CVD in more racially and geographically diverse populations are warranted to elucidate the generalizability of these findings.

Background: Non-genetic factors contribute to differences in diabetes risk across race/ethnic and socioeconomic groups, which raises the question of whether effects of predictors of diabetes are similar across populations. We studied diabetes incidence in the primarily non-Hispanic White Framingham Heart Study (FHS, N = 4066) and the urban, largely immigrant Hispanic Community Health Study/Study of Latinos (HCHS/SOL, N = 6891) Please check if the affiliations are captured and presented correctly., Methods: Clinical, behavioral, and socioeconomic characteristics were collected at in-person examinations followed by seven-day accelerometry. Among individuals without diabetes, Cox proportional hazards regression models (both age- and sex-adjusted, and then multivariable-adjusted for all candidate predictors) identified predictors of incident diabetes over a decade of follow-up, defined using clinical history or laboratory assessments., Results: Four independent predictors were shared between FHS and HCHS/SOL. In each cohort, the multivariable-adjusted hazard of diabetes increased by approximately 50% for every ten-year increment of age and every five-unit increment of body mass index (BMI), and was 50-70% higher among hypertensive than among non-hypertensive individuals (all P < 0.01). Compared with full-time employment status, the multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI) for part-time employment was 0.61 (0.37,1.00) in FHS and 0.62 (0.41,0.95) in HCHS/SOL. Moderate-to-vigorous physical activity (MVPA) was an additional predictor in common observed in age- and sex-adjusted models, which did not persist after adjustment for other covariates (compared with MVPA ≤ 5 min/day, HR for MVPA level ≥ 30 min/day was 0.48 [0.31,0.74] in FHS and 0.74 [0.56,0.97] in HCHS/SOL). Additional predictors found in sex- and age-adjusted analyses among the FHS participants included male gender and lower education, but these predictors were not found to be independent of others in multivariable adjusted models, nor were they associated with diabetes risk among HCHS/SOL adults., Conclusions: The same four independent predictors - age, body mass index, hypertension and employment status - were associated with diabetes risk across two disparate US populations. While the reason for elevated diabetes risk in full-time workers is unclear, the findings suggest that diabetes may be part of the work-related burden of disease. Our findings also support prior evidence that differences by gender and socioeconomic position in diabetes risk are not universally present across populations., (© 2022. The Author(s).)

Importance: Cardiovascular Health (CVH) scores are inversely associated with prevalent subclinical (SubDz) and incident cardiovascular disease (CVD). However, the majority of people who develop CVD have intermediate or ideal CVH scores, while many with poor CVH profiles escape CVD development., Objective: To describe the prevalence of paradoxical relations among CVH, SubDz, and CVD., Design: Cohort study, Framingham Study data collected prospectively (1995-2016)., Setting: Population-based., Participants: 7,627 participants (mean age 49 years, 53% women) attending Offspring examinations 6/7 and Third Generation examinations 1/2., Exposures: CVH score (range 0-14) constructed from poor, intermediate, or ideal status for each metric (smoking, diet, physical activity, blood pressure, body mass index, fasting glucose, total cholesterol); and prevalent SubDz (≥1 of: increased carotid intimal media thickness, CIMT; left ventricular hypertrophy, LVH; microalbuminuria, MA; elevated ankle brachial index, ABI; coronary artery calcium score ≥100,CAC)., Main Outcome(s) and Measure(s): Ideal CVH (scores 12-14), intermediate CVH (scores 8-11), and poor CVH (0-7). We described three distinct paradoxical phenomena, involving combinations of CVH, SubDz, and CVD, and generated CVD incidence rates and predicted CVD probabilities for all combinations., Results: We observed 842 CVD events (median follow-up 13.7 years); 1,663 participants had SubDz. Most individuals with poor CVH (78%) or SubDz (57% for CIMT to 77% for LVH) did not develop CVD on follow-up. Among participants with incident CVD, the majority had intermediate or ideal CVH (68%) or absent SubDz (46% for CAC to 96% for ABI) at baseline. We observed similar paradoxical results in relations between CVH and prevalent SubDz. Poor CVH and prevalent SubDz were each associated with higher CVD incidence rates compared to intermediate or ideal CVH and absent SubDz, respectively. The predicted CVD probability was nearly three-times greater among participants with poor (22%) versus intermediate or ideal CVH (8%). Mean CVD predicted probabilities were nearly three (26% vs. 10% for MA) to six-times (29% vs. 5% for CAC) greater among participants with SubDz versus without SubDz. Findings were consistent within age and sex strata., Conclusions and Relevance: Although poor CVH and SubDz presence are associated with CVD incidence, paradoxical phenomena involving CVH, SubDz, and CVD are frequently prevalent in the community. Further studies to elucidate biological mechanisms underlying these phenomena are warranted., Competing Interests: The authors have declared that no competing interests exist.

Background: In response to the novel Coronavirus Disease 2019 (COVID-19) pandemic, the Department of Veterans Affairs (VA) Million Veteran Program (MVP) organized efforts to better understand the impact of COVID-19 on Veterans by developing and deploying a self-reported survey., Methods: The MVP COVID-19 Survey was developed to collect COVID-19 specific elements including symptoms, diagnosis, hospitalization, behavioral and psychosocial factors and to augment existing MVP data with longitudinal collection of key domains in physical and mental health. Due to the rapidly evolving nature of the pandemic, a multipronged strategy was implemented to widely disseminate the COVID-19 Survey and capture data using both the online platform and mailings., Results: We limited the findings of this paper to the initial phase of survey dissemination which began in May 2020. A total of 729,625 eligible MVP Veterans were invited to complete version 1 of the COVID-19 Survey. As of October 31, 2020, 58,159 surveys have been returned. The mean and standard deviation (SD) age of responders was 71 (11) years, 8.6% were female, 8.2% were Black, 5.6% were Hispanic, and 446 (0.8%) self-reported a COVID-19 diagnosis. Over 90% of responders reported wearing masks, practicing social distancing, and frequent hand washing., Conclusion: The MVP COVID-19 Survey provides a systematic collection of data regarding COVID-19 behaviors among Veterans and represents one of the first large-scale, national surveillance efforts of COVID-19 in the Veteran population. Continued work will examine the overall response to the survey with comparison to available VA health record data., Competing Interests: The authors have declared that no competing interests exist.

Background The epidemiology of hypertension subtypes has not been well characterized in the recent era. Methods and Results We delineated the prevalence, predictors, progression, and prognostic significance of hypertension subtypes in 8198 Framingham Heart Study participants (mean age, 46.5 years; 54% women). The prevalence of hypertension subtypes was as follows: nonhypertensive (systolic blood pressure [SBP] <140 mm Hg and diastolic blood pressure [DBP] <90 mm Hg), 79%; isolated systolic hypertension (ISH; SBP ≥140 mm Hg and DBP <90 mm Hg), 8%; isolated diastolic hypertension (SBP <140 mm Hg and DBP ≥90 mm Hg), 4%; and systolic-diastolic hypertension (SDH; SBP ≥140 mm Hg and DBP ≥90 mm Hg), 9%. The prevalence of ISH and SDH increased with age. Analysis of a subsample of nonhypertensive participants demonstrated that increasing age, female sex, higher heart rate, left ventricular mass, and greater left ventricular concentricity were predictors of incident ISH and SDH. Higher baseline DBP was associated with the risk of developing isolated diastolic hypertension and SDH, whereas higher SBP was associated with all 3 hypertension subtypes. On follow-up (median, 5.5 years), isolated diastolic hypertension often reverted to nonhypertensive BP (in 42% of participants) and ISH progressed to SDH (in 26% of participants), whereas SDH frequently transitioned to ISH (in 20% of participants). During follow-up (median, 14.6 years), 889 participants developed cardiovascular disease. Compared with the nonhypertensive group (referent), ISH (adjusted hazard ratio [HR], 1.57; 95% CI, 1.30-1.90) and SDH (HR, 1.66; 95% CI, 1.36-2.01) were associated with increased cardiovascular disease risk, whereas isolated diastolic hypertension was not (HR, 1.03; 95% CI, 0.68-1.57). Conclusions Hypertension subtypes vary in prevalence with age, are dynamic during short-term follow-up, and exhibit distinctive prognoses, underscoring the importance of blood pressure subphenotyping.

Objective: To examine the association between intakes of sodium and potassium and the ratio of sodium to potassium and incident myocardial infarction and stroke. Design, Setting and Participants: Prospective cohort study of 180,156 Veterans aged 19 to 107 years with plausible dietary intake measured by food frequency questionnaire (FFQ) who were free of cardiovascular disease (CVD) and cancer at baseline in the VA Million Veteran Program (MVP). Main outcome measures: CVD defined as non-fatal myocardial infarction (MI) or acute ischemic stroke (AIS) ascertained using high-throughput phenotyping algorithms applied to electronic health records. Results: During up to 8 years of follow-up, we documented 4090 CVD cases (2499 MI and 1712 AIS). After adjustment for confounding factors, a higher sodium intake was associated with a higher risk of CVD, whereas potassium intake was inversely associated with the risk of CVD [hazard ratio (HR) comparing extreme quintiles, 95% confidence interval (CI): 1.09 (95% CI: 0.99−1.21, p trend = 0.01) for sodium and 0.87 (95% CI: 0.79−0.96, p trend = 0.005) for potassium]. In addition, the ratio of sodium to potassium (Na/K ratio) was positively associated with the risk of CVD (HR comparing extreme quintiles = 1.26, 95% CI: 1.14−1.39, p trend < 0.0001). The associations of Na/K ratio were consistent for two subtypes of CVD; one standard deviation increment in the ratio was associated with HRs (95% CI) of 1.12 (1.06−1.19) for MI and 1.11 (1.03−1.19) for AIS. In secondary analyses, the observed associations were consistent across race and status for diabetes, hypertension, and high cholesterol at baseline. Associations appeared to be more pronounced among participants with poor dietary quality. Conclusions: A high sodium intake and a low potassium intake were associated with a higher risk of CVD in this large population of US veterans.

Background: Guidelines emphasize screening people with elevated BP for the presence of end-organ damage., Methods: We characterized the prevalence, correlates, and prognosis of hypertension-mediated organ damage (HMOD) in the community-based Framingham Study. 7898 participants (mean age 51.6 years, 54% women) underwent assessment for the following HMOD: electrocardiographic and echocardiographic left ventricular hypertrophy, abnormal brain imaging findings consistent with vascular injury, increased carotid intima-media thickness, elevated carotid-femoral pulse wave velocity, reduced kidney function, microalbuminuria, and low ankle-brachial index. We characterized HMOD prevalence according to blood pressure (BP) categories defined by four international BP guidelines. Participants were followed up for incidence of cardiovascular disease., Results: The prevalence of HMOD varied positively with systolic BP and pulse pressure but negatively with diastolic BP; it increased with age, was similar in both sexes, and varied across BP guidelines based on their thresholds defining hypertension. Among participants with hypertension, elevated carotid-femoral pulse wave velocity was the most prevalent HMOD (40%-60%), whereas low ankle-brachial index was the least prevalent (<5%). Left ventricular hypertrophy, reduced kidney function, microalbuminuria, increased carotid intima-media thickness, and abnormal brain imaging findings had an intermediate prevalence (20%-40%). HMOD frequently clustered within individuals. On follow-up (median, 14.1 years), there were 384 cardiovascular disease events among 5865 participants with concurrent assessment of left ventricular mass, carotid-femoral pulse wave velocity, kidney function, and microalbuminuria. For every BP category above optimal (referent group), the presence of HMOD increased cardiovascular disease risk compared with its absence., Conclusions: The prevalence of HMOD varies across international BP guidelines based on their different thresholds for defining hypertension. The presence of HMOD confers incremental prognostic information regarding cardiovascular disease risk at every BP category.

Objective: Gut microbiota-derived metabolites are involved in intestinal inflammation, which can affect the development of atherosclerotic plaques. Previous studies have shown that oat fiber can delay the progression of atherosclerosis via improving lipid metabolism. The aim of this study was to evaluate how oat fiber acted on gut microbiota-derived metabolites, inhibited intestinal inflammation, and protected the intestinal mucosal barrier., Methods: Male low-density lipoprotein receptor knock-out (LDLR -/- ) mice were fed a high-fat/cholesterol diet with or without oat fiber for 14 wk. Histopathology of the aorta was detected by Oil Red O staining, and the small intestine mucosal pathology was measured through hematoxylin and eosin staining. Non-targeted metabolomics of feces was performed using liquid chromatography-mass spectrometry. Western blot method was used to assess the relative levels of the proteins involved in the toll-like receptor (TLR)4 signal pathway and intestinal mucosal barrier in interest tissues., Results: Pathologically, oat fiber reversed the increment of the atherosclerotic lesion and ameliorated intestinal mucosal barrier in LDLR -/- mice. Oat fiber regulated the levels of gut microbiota-derived metabolites along with a decrease in isobutyrylcarnitine, valerylcarnitine, 1-methylguanosine, and 2-methylguanosine, and an increase in l-tyrosine and niacinamide. Notably, oat fiber blocked the TLR4 signal pathway and decreased the expression of nuclear factor-κB p65 in both the aorta and gut tissues. Also, oat fiber raised the expression of tight junction proteins including ZO-1 and occludin., Conclusion: Taken together, the present study revealed that oat fiber feeding effectively attenuated the development of atherosclerosis, at least partly via affecting gut microbiota-derived metabolites, inhibiting the intestinal inflammatory response, and maintaining the integrity of the intestinal mucosal barrier., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Frailty is associated with an increased risk of all-cause mortality and cardiovascular (CV) events. Limited data exist from the modern era of CV prevention on the relationship between frailty and CV mortality. We hypothesized that frailty is associated with an increased risk of CV mortality., Methods and Results: All US Veterans aged ≥65 years who were regular users of Veteran Affairs care from 2002 to 2017 were included. Frailty was defined using a 31-item previously validated frailty index, ranging from 0 to 1. The primary outcome was CV mortality with secondary analyses examining the relationship between frailty and CV events (myocardial infarction, stroke, revascularization). Survival analysis models were adjusted for age, sex, ethnicity, geographic region, smoking, hyperlipidaemia, statin use, and blood pressure medication use. There were 3 068 439 US Veterans included in the analysis. Mean age was 74.1 ± 5.8 years in 2002, 76.0 ± 8.3 years in 2014, 98% male, and 87.5% White. In 2002, the median (interquartile range) frailty score was 0.16 (0.10-0.23). This increased and stabilized to 0.19 (0.10-0.32) for 2006-14. The presence of frailty was associated with an increased risk of CV mortality at every stage of frailty. Frailty was associated with an increased risk of myocardial infarction and stroke, but not revascularization., Conclusion: In this population, both the presence and severity of frailty are tightly correlated with CV death, independent of underlying CV disease. This study is the largest and most contemporary evaluation of the relationship between frailty and CV mortality to date. Further work is needed to understand how this risk can be diminished., Key Question: Can an electronic frailty index identify adults aged 65 and older who are at risk of CV mortality and major CV events?, Key Finding: Among 3 068 439 US Veterans aged 65 and older, frailty was associated with an increased risk of CV mortality at every level of frailty. Frailty was also associated with an increased risk of myocardial infarction and stroke, but not revascularization., Take Home Message: Both the presence and severity of frailty are associated with CV mortality and major CV events, independent of underlying CV disease., (Published by Oxford University Press on behalf of the European Society of Cardiology 2021. This work is written by US Government employees and is in the public domain in the US.)

A copper-catalyzed remote benzylic C-H functionalization strategy enabling 1,2-difunctionalization of alkenes with 2-methylbenzeneamides and nucleophiles, including alcohols, indoles, pyrroles, and the intrinsic amino groups, is reported, which is characterized by its redox-neutral conditions, exquisite site-selectivity, broad substrate scope, and wide utilizations of late-stage modifying bioactive molecules. This reaction proceeds through nitrogen-centered radical generation, hydrogen atom transfer, benzylic radical addition across the alkenes, single-electron oxidation, and carbocation electrophilic course cascades. While using external nucleophiles manipulates three-component alkene alkylalkoxylation and alkyl-heteroarylation with 2-methylbenzeneamides to access dialkyl ethers, 3-alkylindoles, and 3-alkylpyrroles, omitting the external nucleophiles results in two-component alkylamidation ([5+2] annulation) of alkenes with 2-methylbenzeneamides to benzo-[ f ][1,2]thiazepine 1,1-dioxides.

Calcium oxalate (CaOx) is a major contributor to urolithiasis, one of the most common urological diseases. Our previous study has shown that Klotho rs3752472 polymorphism correlates with an increased risk of CaOx-related urolithiasis in human cohorts. This study aims to identify the effect of Klotho rs3752472 polymorphism on the renal epithelium injury caused by CaOx. A rat urolithiasis model was established and validated. Renal function was assessed, and histological examination was performed. The distribution and expression of Klotho in the rat model were detected by immunohistochemical staining and western blotting analysis. A renal epithelial cell line (HK2) was used and intervened by COM crystals with several concentrations and time points. Expression of Klotho and key mediators in Wnt/β-catenin pathway were assessed by Western blotting analysis. Wide-type and mutated plasmids of Klotho rs3752472 were added in the cell culture, and the activation of Wnt/β-catenin signaling was tested. Finally, Wide-type and mutated plasmids of Klotho rs3752472 were adoptively transferred to the rat model, and the expression of Klotho was verified. In the rat model, Klotho was mainly distributed in the renal tubular area, which significantly declined in the urolithiasis group. In vitro, COM crystals significantly inhibited the expression of Klotho and induced remarkable renal epithelial cell injury. The mutation of Klotho rs3752472 can notably enhance the expression of Klotho, as well as the protection from renal epithelial cell injury and the inhibition of Wnt/β-catenin signaling pathway. After adoptively transferred to the rat urolithiasis model, similar results were observed for the mutation of Klotho rs3752472. Klotho was significantly correlated with the renal epithelial cell injury induced by CaOx crystals. Furthermore, the mutation of Klotho rs3752472 can remarkably enhance the expression of Klotho in renal tissues and cells, and subsequently protect the renal epithelial cell from the formation of CaOx crystals through the inhibition of Wnt/β-catenin signaling pathway., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

[Figure: see text].

Importance: The associations of estimated cardiorespiratory fitness (eCRF) during midlife with subclinical atherosclerosis, arterial stiffness, incident cardiometabolic disease, and mortality are not well understood., Objective: To examine associations of midlife eCRF with subclinical atherosclerosis, arterial stiffness, incident cardiometabolic disease, and mortality., Design, Setting, and Participants: This cohort study included 2962 participants in the Framingham Study Second Generation (conducted between 1979 and 2001). Data were analyzed from January 2020 to June 2020., Exposures: eCRF was calculated using sex-specific algorithms (including age, body mass index, waist circumference, physical activity, resting heart rate, and smoking) and was categorized as: (1) tertiles of standardized eCRF at examination cycle 7 (1998 to 2001); (2) tertiles of standardized average eCRF between examination cycles 2 and 7 (1979 to 2001); and (3) eCRF trajectories between examination cycles 2 and 7, with the lowest tertile or trajectory (ie, low eCRF) as referent group., Main Outcomes and Measures: Subclinical atherosclerosis (carotid intima-media thickness [CIMT], coronary artery calcium [CAC] score); arterial stiffness (carotid-femoral pulse wave velocity [-1000/CFPWV]); incident hypertension, diabetes, chronic kidney disease (CKD), cardiovascular disease (CVD), and mortality after examination cycle 7., Results: A total of 2962 participants were included in this cohort study (mean [SD] age, 61.5 [9.2] years; 1562 [52.7%] women). The number of events or participants at risk after examination cycle 7 (at a mean follow-up of 15 years) was 728 of 1506 for hypertension, 214 of 2268 for diabetes, 439 of 2343 for CKD, 500 of 2608 for CVD, and 770 of 2962 for mortality. Compared with the low eCRF reference value, high single examination eCRF was associated with lower CFPWV (β [SE], -11.13 [1.33] ms/m) and CIMT (β [SE], -0.12 [0.05] mm), and lower risk of hypertension (hazard ratio [HR], 0.63; 95% CI, 0.46-0.85), diabetes (HR, 0.38; 95% CI, 0.23-0.62), and CVD (HR, 0.71; 95% CI, 0.53-0.95), although it was not associated with CKD or mortality. Similarly, compared with the low eCRF reference, high eCRF trajectories and mean eCRF were associated with lower CFPWV (β [SE], -11.85 [1.89] ms/m and -10.36 [1.54] ms/m), CIMT (β [SE], -0.19 [0.06] mm and -0.15 [0.05] mm), CAC scores (β [SE], -0.67 [0.25] AU and -0.63 [0.20] AU), and lower risk of hypertension (HR, 0.54; 95% CI, 0.34-0.87 and HR, 0.48; 95% CI, 0.34-0.68), diabetes (HR, 0.27; 95% CI, 0.15-0.48 and HR, 0.31; 95% CI, 0.18-0.54), CKD (HR, 0.63; 95% CI, 0.40-0.97 and HR, 0.64; 95% CI, 0.44-0.94), and CVD (HR, 0.46; 95% CI, 0.31-0.68 and HR, 0.43; 95% CI, 0.30-0.60). Compared with the reference value, a high eCRF trajectory was associated with lower risk of mortality (HR, 0.69; 95% CI, 0.50-0.95)., Conclusions and Relevance: In this cohort study, higher midlife eCRF was associated with lower burdens of subclinical atherosclerosis and vascular stiffness, and with a lower risk of hypertension, diabetes, chronic kidney disease, cardiovascular disease, and mortality. These findings suggest that midlife eCRF may serve as a prognostic marker for subclinical atherosclerosis, arterial stiffness, cardiometabolic health, and mortality in later life.

Background Data are limited on the association of mildly reduced estimated glomerular filtration rate (eGFR 60-89 mL/min per 1.73 m 2 ) with cardiovascular disease (CVD) in the community. Methods and Results We evaluated 3066 Framingham Offspring Study participants (55% women, mean age 58 years), without clinical CVD. Using multivariable regression, we related categories of mildly reduced eGFR (80-89, 70-79, or 60-69 versus ≥90 mL/min per 1.73 m 2 [referent]) to prevalent coronary artery calcium, carotid intima media thickness, and left ventricular hypertrophy, and to circulating concentrations of cardiac stress biomarkers. We related eGFR categories to CVD incidence and to progression to ≥Stage 3 chronic kidney disease (eGFR <60 mL/min per 1.73 m 2 ) using Cox regression. Individuals with eGFR 60-69 mL/min per 1.73 m 2 (n=320) had higher coronary artery calcium score (odds ratio 1.69; 95% CI 1.02-2.80) compared with the referent group. Individuals with eGFR 60-69 and 70-79 mL/min per 1.73 m 2 had higher blood growth differentiating factor-15 concentrations (β=0.131 and 0.058 per unit-increase in log-biomarker, respectively). Participants with eGFR 60-69 and 80-89 mL/min per 1.73 m 2 had higher blood B-type natriuretic peptide concentrations (β=0.119 and 0.116, respectively). On follow-up (median 16 years; 691 incident CVD and 252 chronic kidney disease events), individuals with eGFR 60-69 and 70-79 mL/min per 1.73 m 2 experienced higher CVD incidence (hazard ratio [HR], 1.40; 95% CI, 1.02-1.93 and 1.45, 95% CI, 1.05-2.00, respectively, versus referent). Participants with eGFR 60-69 mL/min per 1.73 m 2 experienced higher chronic kidney disease incidence (HR, 2.94; 95% CI, 1.80-4.78 versus referent). Conclusions Individuals with mildly reduced eGFR 60-69 mL/min per 1.73 m 2 have a higher burden of subclinical atherosclerosis cross-sectionally, and a greater risk of CVD and chronic kidney disease progression prospectively. Additional studies are warranted to confirm our findings.

The neonatal heart possesses the ability to proliferate and the capacity to regenerate after injury; however, the mechanisms underlying these processes are not fully understood. Melatonin has been shown to protect the heart against myocardial injury through mitigating oxidative stress, reducing apoptosis, inhibiting mitochondrial fission, etc. In this study, we investigated whether melatonin regulated cardiomyocyte proliferation and promoted cardiac repair in mice with myocardial infarction (MI), which was induced by ligation of the left anterior descending coronary artery. We showed that melatonin administration significantly improved the cardiac functions accompanied by markedly enhanced cardiomyocyte proliferation in MI mice. In neonatal mouse cardiomyocytes, treatment with melatonin (1 μM) greatly suppressed miR-143-3p levels. Silencing of miR-143-3p stimulated cardiomyocytes to re-enter the cell cycle. On the contrary, overexpression of miR-143-3p inhibited the mitosis of cardiomyocytes and abrogated cardiomyocyte mitosis induced by exposure to melatonin. Moreover, Yap and Ctnnd1 were identified as the target genes of miR-143-3p. In cardiomyocytes, inhibition of miR-143-3p increased the protein expression of Yap and Ctnnd1. Melatonin treatment also enhanced Yap and Ctnnd1 protein levels. Furthermore, Yap siRNA and Ctnnd1 siRNA attenuated melatonin-induced cell cycle re-entry of cardiomyocytes. We showed that the effect of melatonin on cardiomyocyte proliferation and cardiac regeneration was impeded by the melatonin receptor inhibitor luzindole. Silencing miR-143-3p abrogated the inhibition of luzindole on cardiomyocyte proliferation. In addition, both MT1 and MT2 siRNA could cancel the beneficial effects of melatonin on cardiomyocyte proliferation. Collectively, the results suggest that melatonin induces cardiomyocyte proliferation and heart regeneration after MI by regulating the miR-143-3p/Yap/Ctnnd1 signaling pathway, providing a new therapeutic strategy for cardiac regeneration.

Background: The risk factors associated with the stages of Coronavirus Disease-2019 (COVID-19) disease progression are not well known. We aim to identify risk factors specific to each state of COVID-19 progression from SARS-CoV-2 infection through death., Methods and Results: We included 648,202 participants from the Veteran Affairs Million Veteran Program (2011-). We identified characteristics and 1,809 ICD code-based phenotypes from the electronic health record. We used logistic regression to examine the association of age, sex, body mass index (BMI), race, and prevalent phenotypes to the stages of COVID-19 disease progression: infection, hospitalization, intensive care unit (ICU) admission, and 30-day mortality (separate models for each). Models were adjusted for age, sex, race, ethnicity, number of visit months and ICD codes, state infection rate and controlled for multiple testing using false discovery rate (≤0.1). As of August 10, 2020, 5,929 individuals were SARS-CoV-2 positive and among those, 1,463 (25%) were hospitalized, 579 (10%) were in ICU, and 398 (7%) died. We observed a lower risk in women vs. men for ICU and mortality (Odds Ratio (95% CI): 0.48 (0.30-0.76) and 0.59 (0.31-1.15), respectively) and a higher risk in Black vs. Other race patients for hospitalization and ICU (OR (95%CI): 1.53 (1.32-1.77) and 1.63 (1.32-2.02), respectively). We observed an increased risk of all COVID-19 disease states with older age and BMI ≥35 vs. 20-24 kg/m2. Renal failure, respiratory failure, morbid obesity, acid-base balance disorder, white blood cell diseases, hydronephrosis and bacterial infections were associated with an increased risk of ICU admissions; sepsis, chronic skin ulcers, acid-base balance disorder and acidosis were associated with mortality., Conclusions: Older age, higher BMI, males and patients with a history of respiratory, kidney, bacterial or metabolic comorbidities experienced greater COVID-19 severity. Future studies to investigate the underlying mechanisms associated with these phenotype clusters and COVID-19 are warranted., Competing Interests: The authors have declared that no competing interests exist.

We have developed a new radical-mediated alkoxypolyhaloalkylation of styrenes with polychloroalkanes and alcohols for the facile synthesis of complex polyhaloalkanes. 4-Methoxybenzenediazonium tetrafluoroborate is a good radical initiator for this transformation. This protocol is well applied to the late-stage functionalization of complex molecules, including vitamin E, estrone and cholesterol derivatives.

Background and Aims: Cardiac and vascular growth factors (GF) may influence myocardial remodeling through cardiac growth and angiogenic effects. We hypothesized that concentrations of circulating GF are associated with cardiac remodeling traits., Methods: We related blood concentrations of vascular endothelial GF (VEGF), VEGFR-1 (sFlt1), angiopoietin 2 (Ang-2), soluble angiopoietin type-2 receptor (sTie2), hepatocyte GF (HGF), insulin-like GF (IGF)-1, IGF binding protein (IGFBP)-3, and growth differentiation factor-15 (GDF-15) to echocardiographic traits in 3151 Framingham Study participants (mean age 40 years, 55% women). We evaluated the following measures: left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), global longitudinal strain (GLS), mitral E/e', and aortic root diameter (AoR). All biomarker values were sex-standardized., Results: In multivariable-adjusted analyses, higher GDF-15 concentrations were associated with higher log-LVMi (β = 0.009 per SD, P = 0.01). Similarly, sTie2 concentrations were positively associated with log-E/e' (β = 0.011 per SD, P = 0.04). IGF-1 and Ang-2 concentrations were positively and negatively associated with GLS, respectively (β IGF-1  = 0.16 per SD and β Ang-2  = -0.15 per SD, both P < 0.05), whereas higher sFlt1 and Ang-2 levels were associated with smaller log-AoR (β sFlt1  = -0.004 per SD and β Ang-2  = -0.005 per SD, respectively; P < 0.05)., Conclusion: In our large community-based sample, we observed patterns of associations between several circulating vascular GF and cardiac remodeling indices that are consistent with the known biological effects of these pro- and anti-angiogenic factors on the myocardium and conduit arteries. Additional studies are warranted to replicate our findings and assess their prognostic significance., Competing Interests: Declaration of Competing Interest Dr. Mitchell is the owner of Cardiovascular Engineering Inc., a company that develops and manufactures devices to measure vascular stiffness. He has also served as consultant for and received honoraria and grants from Merck, Servier and Novartis. The other authors do not have competing interests to declare., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background Exercise stress tests are conventionally performed to assess risk of coronary artery disease. Using the FHS (Framingham Heart Study) Offspring cohort, we related blood pressure (BP) and heart rate responses during and after submaximal exercise to the incidence of heart failure (HF). Methods and Results We evaluated Framingham Offspring Study participants (n=2066; mean age, 58 years; 53% women) who completed 2 stages of an exercise test (Bruce protocol) at their seventh examination (1998-2002). We measured pulse pressure, systolic BP, diastolic BP, and heart rate responses during stage 2 exercise (2.5 mph at 12% grade). We calculated the changes in systolic BP, diastolic BP, and heart rate from stage 2 to recovery 3 minutes after exercise. We used Cox proportional hazards regression to relate each standardized exercise variable (during stage 2, and at 3 minutes of recovery) individually to HF incidence, adjusting for standard risk factors. On follow-up (median, 16.8 years), 85 participants developed new-onset HF. Higher exercise diastolic BP was associated with higher HF with reduced ejection fraction (ejection fraction <50%) risk (hazard ratio [HR] per SD increment, 1.26; 95% CI, 1.01-1.59). Lower stage 2 pulse pressure and rapid postexercise recovery of heart rate and systolic BP were associated with higher HF with reduced ejection fraction risk (HR per SD increment, 0.73 [95% CI, 0.57-0.94]; 0.52 [95% CI, 0.35-0.76]; and 0.63 [95% CI, 0.47-0.84], respectively). BP and heart rate responses to submaximal exercise were not associated with risk of HF with preserved ejection fraction (ejection fraction ≥50%). Conclusions Accentuated diastolic BP during exercise with slower systolic BP and heart rate recovery after exercise are markers of HF with reduced ejection fraction risk.

Racial/ethnic health disparities persist among veterans despite comparable access and quality of care. We describe racial/ethnic differences in self-reported health characteristics among 437,413 men and women (mean age (SD) = 64.5 (12.6), 91% men, 79% White) within the Million Veteran Program. The Cochran-Mantel-Haenszel test and linear mixed models were used to compare age-standardized frequencies and means across race/ethnicity groups, stratified by gender. Black, Hispanic, and Other race men and women reported worse self-rated health, greater VA healthcare utilization, and more combat exposure than Whites. Compared to White men, Black and Other men reported more circulatory, musculoskeletal, mental health, and infectious disease conditions while Hispanic men reported fewer circulatory and more mental health, infectious disease, kidney, and neurological conditions. Compared to White women, Black women reported more circulatory and infectious disease conditions and Other women reported more infectious disease conditions. Smoking rates were higher among Black men, but lower for other minority groups compared to Whites. Minority groups were less likely to drink alcohol and had lower physical fitness than Whites. By identifying differences in burden of various health conditions and risk factors across different racial/ethnic groups, our findings can inform future studies and ultimately interventions addressing disparities.

We have disclosed a new radical-mediated decarboxylative C(sp 3 )-N cross-coupling of diacyl peroxides with nitrogen nucleophiles. The primary and secondary alkyl radicals derived from corresponding diacyl peroxides were generated by copper catalysis or by merging copper catalysis and photoredox catalysis, respectively. Various N -alkyl nitrogen nucleophiles, including indazoles, triazoles, indoles, purine, carbazole, anilines, and sulfonamide, were provided with a broad substrate scope and good functional group tolerance.

We have developed a new oxidative decarboxylation of cinnamic acids with 4-alkyl-1,4-dihydropyridines to construct C(sp3)-C(sp2) bonds in the presence of copper catalyst and dicumyl peroxide (DCP). A variety of internal alkenes have been obtained with mild conditions, broad substrate scope and excellent functional group tolerance. This method has significant potential for application by using inexpensive and stable cinnamic acids instead of alkenyl halides and nitro-olefins.

Aims: We sought to describe the frequency, type and timing of clinical events, and delineate patterns in their transitions, after a first episode of heart failure (HF)., Methods and Results: In 1036 Framingham participants with new-onset HF (mean age 79 years; 53% women), we used mixture models to estimate probabilities of, and time to cardiac death, other cardiovascular disease (CVD) death, recurrent HF, cardiac events and other CVD events, accounting for age, sex, HF type (preserved vs. reduced ejection fraction), and prevalent cardiac/CVD events. The most common first events after new-onset HF were cardiac (36%), recurrent HF (28%) and death (29%). Compared with recurrent HF (referent transition state), prevalent cardiac events were associated with higher odds of fatal [odds ratio (OR) 1.90, 95% confidence interval (CI) 1.11-3.23] and non-fatal (OR 2.13, 95% CI 1.52-3.00) cardiac events; prevalent CVD increased odds of other CVD death (OR 1.90, 95% CI 1.04-3.47). Among 715 participants without a fatal initial event, there were 3337 distinct epochs (inter-event time periods), with median 3.0 epochs/participant [49% cardiac (n = 1639); 27% recurrent HF (n = 912)]. Median inter-event times varied between 12 to 285 days (recurrent HF to other CVD death and non-fatal other CVD, respectively). Prior HF, cardiac and other CVD events significantly increased odds of developing the same event-type (OR ∼ 5-7-fold), with shortened time to recurrence, indicating 'rapid cycling loops' of the same event type. HF type did not impact the nature or timing of future events., Conclusions: Comorbidities but not HF type impact clinical course of HF by influencing the type and timing of subsequent events, denoting 'natural history loops' within the overall HF population., (© 2020 European Society of Cardiology.)

A general, ideal atom utilization electrochemical technology to enable alkene alkoxyhalogenation and organohalide dehalogenation in one pot is presented. This technology is highlighted by convergent strategy integrating several reactions, such as alkene alkoxyhalogenation, organohalide dehalogenation, and dehalogenation deuteration. Experimental data suggest that alkenes have the lowest oxidation potential, which lead to anodic conversion of the C═C bond to the radical cation intermediates, and cathodic transformations of organohalides, including alkyl and aryl halides, as the nucleophilic halogen sources.

Background Offspring of parents with premature cardiovascular disease (CVD) have an increased risk of developing subclinical and clinical CVD. It is unclear whether this association differs by vascular beds in the offspring or by the age cut points used to define premature parental CVD. Methods and Results Using 3 generations of Framingham Heart Study participants, we assessed prevalent coronary artery calcification, the progression of coronary artery calcification over 6.1 years (median), carotid intima media thickness and the ankle-brachial index in 1046 offspring of parents with premature CVD before age 70 years, in 1618 offspring with both parents free of CVD and in 923 offspring with parents with CVD after age 70 years. We used different age cut points (55, 60, 65, and 70 years) to define premature parental CVD. In multivariable-adjusted models, offspring of parents with premature CVD (onset before age 65 years) displayed greater odds for prevalent coronary artery calcification (odds ratio [OR], 1.81; 95% CI, 1.35-2.43), higher carotid intima media thickness (OR, 1.50; 95% CI, 0.92-2.44) and lower ankle-brachial index (OR, 1.89; 95% CI, 1.00-3.58). These associations were generally consistent across different age cut points used to define premature parental CVD. The association with the progression of coronary artery calcification was less consistent. Conclusions Parental premature CVD is associated with increased subclinical CVD burden in the offspring, with consistent relations across different vascular beds and for different age cut points used to define premature parental CVD. Future studies should evaluate whether screening for subclinical CVD traits is warranted in offspring with premature parental CVD.

Background: Ruptured aortic aneurysm and aortic dissections are potentially preventable disorders associated with high mortality. Screening of individuals at risk may translate into elective surgical interventions and lowered mortality. It is uncertain if the risk of aortic dilation of varying degrees aggregates within families., Methods: We investigated the risk of having thoracic and abdominal aortic sizes in the highest quartile (measured by computed tomography scans and indexed for body size) if at least 1 parent did so in the Framingham Heart Study cohorts, and estimated the incidence rates and hazard ratios of developing aortic aneurysm or dissection among first-degree relatives of those with aortic aneurysm or dissection, in comparison with age- and sex-matched controls (1:10 for aortic aneurysm and 1:100 for aortic dissection) using the Danish nationwide administrative registries., Results: In the Framingham Heart Study, offspring (n=235) whose parent(s) had a sex- and age-standardized aortic size in the upper quartile had a multivariable-adjusted ≈3-fold increased odds ratio of belonging to the upper quartile themselves. In Denmark, a total of 68 939 individuals (mean age, 42 years) had a first-degree relative with aortic aneurysm and 7209 persons (mean age, 39 years) had a first-degree relative with aortic dissection. During an average follow-up of 7 years, first-degree relatives of patients with aortic aneurysm and dissection had a hazard ratio of 6.70 (95% CI, 5.96-7.52) for developing aortic aneurysm and a hazard ratio of 9.24 (95% CI, 5.53-15.44) for dissection in comparison with matched controls. These estimates remained unchanged on adjusting for several comorbidities, including prevalent hypertension, bicuspid aortic valve, and the Marfan syndrome. For both aortic aneurysm and dissections, the absolute event rates approached 1 per 1000 person-years for first-degree relatives versus 11 to 13 (aortic aneurysm) and 2 to 3 (aortic dissections) per 100 000 person-years among controls., Conclusions: Increased aortic size, a precursor of aortic aneurysm and a risk factor for dissection, clusters in families. The incidence rates of aortic aneurysm and dissections approach the incidence rates of other common cardiovascular conditions in first-degree relatives, supporting the use of systematic screening for these conditions.

A new external oxidant-free electrochemical dehydrogenative cross-coupling of xanthenes and ketones for the preparation of functionalized 9-alkyl-9H-xanthenes was developed. This method enables the formation of a new C(sp 3 )-C(sp 3 ) bond through release of H 2 as the major byproduct at room temperature, and features mild conditions, high atom economy, excellent functional-group tolerance, scalability and facile applications in pharmaceutical chemistry.