Research trends in lipid-lowering therapies for coronary heart disease combined with hyperlipidemia: a bibliometric study and visual analysis.

Background: Cardiovascular disease (CVD) poses a significant global health and economic challenge, with atherosclerosis being a primary cause. Over the past 40 years, substantial research has been conducted into the prevention and reversal of atherosclerosis, resulting in the development of lipid-lowering agents such as statins and fibrates. Despite the extensive literature and formulation of numerous therapeutic guidelines in this domain, a comprehensive bibliometric analysis of the current research landscape and trends has not been performed. This study aimed to elucidate the evolution and milestones of research into lipid-lowering treatments for coronary heart disease (CHD) in conjunction with hyperlipidemia through bibliometric analysis, offering insights into future directions for treatment strategies. Methods: This study examined publications from 1986 to 2023 retrieved from the Web of Science database (Core Collection). Utilizing tools such as VOSviewer, Pajek, and CiteSpace, we analyzed publication and citation numbers, H-indexes, contributions by countries and institutions, authorship, journal sources, and keyword usage to uncover research trajectories and areas of focus. Results: Our analysis of 587 publications revealed a recent surge in research output, particularly post-2003. The American Journal of Cardiology published the highest number of studies, with 40 articles, whereas Circulation received the highest number of citations (6,266). Key contributors included the United States, Japan, and China, with the United States leading in citation numbers and the H-index. Harvard University and Leiden University emerged as pivotal institutions, and Professors J. Wouter Jukema and Robert P. Giugliano were identified as leading experts. Keyword analysis disclosed five thematic clusters, indicating a shift in research towards new drug combinations and strategies, signaling future research directions. Conclusion: The last 4 decades have seen a notable rise in publications on lipid-lowering therapies for CHD and hyperlipidemia, with the United States retaining world-leading status. The increase in international collaboration aids the shift towards research into innovative lipid-lowering agents and therapeutic approaches. PCSK9 inhibitors and innovative combination therapies, including antisense oligonucleotides and angiopoietin-like protein 3 inhibitors, provide avenues for future research, intending to maximize the safety and efficacy of treatment approaches.

Modular synthesis of pentacyclic-fused pyranoquinoliziniums as organelle-selective fluorescent probes.

On basis of their unique chemical and photophysical properties, and excellent biological activities, quinoliziniums have been widely used in various research fields. Herein, modular synthetic strategies for efficient synthesis of novel fluorescent quinoliziniums by using one-pot and stepwise rhodium(III)-catalyzed C-H annulations were developed. In the one-pot synthesis, the reaction between 2-aryl-4-quinolones (1) and 1,2-diarylalkynes (2) proceeded in a chemo- and regioselective manner to give quinolinone-fused isoquinolines (3) and pentacyclic-fused pyranoquinoliziniums (4). The structural diversity of pentacyclic-fused pyranoquinoliziniums (4) was expanded by the stepwise synthesis from 3 and 2, allowing the strategic incorporation of electron-donating (OMe and OH) and electron-withdrawing (Cl) substituents on the top and bottom parts of the pyranoquinoliziniums (4). These newly synthesized pyranoquinoliziniums (4) exhibited tunable absorptions (455-532 nm), emissions (520-610 nm), fluorescence lifetime (0.3-5.6 ns), large Stokes shifts (up to 120 nm), and excellent fluorescence quantum yields (up to 0.73) upon adjusting the different substituents. The the unique arrangement of N and O atoms and extended π-conjugation of 4 could cause the relocation of HOMO comparing with our previous quinoliziniums. Importantly, pyranoquinoliziniums (4a-4g and 4i) targeted the mitochondria, while 4h was localized in lysosome. Due to the remarkable photophysical properties and the potential for organelle targeting of the novel class of quinoliziniums, they could be further applied for biological, chemical and material applications.

Development of a Highly Adaptive Miniature Piezoelectric Robot Inspired by Earthworms.

Miniature resonant piezoelectric robots have the advantages of compact structure, fast response, high speed, and easy control, which have attracted the interest of many scholars in recent years. However, piezoelectric robots usually suffer from the problem of poor adaptability due to the micron-level amplitude at the feet. Inspired by the fact that earthworms have actuation trajectories all around their bodies to move flexibly under the ground, a miniature piezoelectric robot with circumferentially arranged driving feet to improve adaptability is proposed. Notably, a longitudinal-vibration-compound actuation principle with multilegged collaboration is designed to achieve the actuation trajectories around the robot, similar to the earthworms. The structure and operating principle are simulated by the finite element method, and the prototype is fabricated. The robot weighs 22.7 g and has dimensions of 35.5 × 36.5 × 47 mm3. The robot is tethered to an ultrasonic power supply, and the experimental results show that the speed reaches 179.35 mm s-1  under an exciting signal with a frequency of 58.5 kHz and a voltage of 200 Vp-p. High adaptability is achieved by the proposed robot, it can move on flat, fold, concave, and convex surfaces, and even in an inclined or rotating tube.

Genotype and Phenotype Characteristics of 58 Cases of Mitochondrial Epilepsy with Nuclear DNA Mutations in Children.

OBJECTIVE: Identify the genotype and clinical characteristics of mitochondrial epilepsy caused by nDNA mutations in Chinese children and explore the treatment and prognosis of the condition. STUDY DESIGN: This is a retrospective cohort study conducted at a single center, including patients diagnosed with an established nDNA mutation-associated primary mitochondrial disease between October 2012 and March 2023 who also met the practical clinical definition of epilepsy published by the ILAE in 2014. RESULTS: Of the 58 patients identified, 74.1% had an onset before the age of 1 year and 63.8% had seizures as their initial symptom. Developmental and epileptic encephalopathy (DEE) (31%) are the most common phenotypes. The most frequently observed MRI abnormalities include abnormal signal asymmetry in the bilateral basal ganglia and/or brainstem (34.7%), as well as brain atrophy, myelin sheath dysplasia, and corpus callosum dysplasia (32.7%). Of the 40 patients followed, seizure treatment was effective in 18 of the cases, while it was ineffective in 22. The mitochondrial DNA depletion syndrome (MDS) was found to be more difficult to control seizures than other phenotypes (P < 0.05). Additionally, the MDS was associated with a significantly higher mortality rate compared to alternative phenotypes (P < 0.05). CONCLUSIONS: The onset of mitochondrial epilepsy due to nDNA mutations is early and seizures are the most common initial symptom. DEE is the most common phenotype. Characteristic MRI abnormalities in the brain may be helpful in the diagnosis of primary mitochondrial disease. People with MDS typically face challenges in seizure control and have a poor prognosis.

DNA-Programmed Four-Bit Quaternary Fluorescence Encoding (FLUCO) Enables 51-Colored Bioimaging Analysis.

Color encoding plays a crucial role in painting, digital photography, and spectral analysis. Achieving accurate, target-responsive color encoding at the molecular level has the potential to revolutionize scientific research and technological innovation, but significant challenges persist. Here, we propose a multibit DNA self-assembly system based on computer-aided design (CAD) technology, enabling accurate, target-responsive, amplified color encoding at the molecular level, termed fluorescence encoding (FLUCO). As a model, we establish a quaternary FLUCO system using four-bit DNA self-assembly, which can accurately encode 51 colors, presenting immense potential in applications such as spatial proteomic imaging and multitarget analysis. Notably, FLUCO enables the simultaneous imaging of multiple targets exceeding the limitations of channels using conventional imaging equipment, and marks the integration of computer science for molecular encoding and decoding. Overall, our work paves the way for target-responsive, controllable molecular encoding, facilitating spatial omics analysis, exfoliated cell analysis, and high-throughput liquid biopsy.

A facile DNA coacervate platform for engineering wetting, engulfment, fusion and transient behavior.

Biomolecular coacervates are emerging models to understand biological systems and important building blocks for designer applications. DNA can be used to build up programmable coacervates, but often the processes and building blocks to make those are only available to specialists. Here, we report a simple approach for the formation of dynamic, multivalency-driven coacervates using long single-stranded DNA homopolymer in combination with a series of palindromic binders to serve as a synthetic coacervate droplet. We reveal details on how the length and sequence of the multivalent binders influence coacervate formation, how to introduce switching and autonomous behavior in reaction circuits, as well as how to engineer wetting, engulfment and fusion in multi-coacervate system. Our simple-to-use model DNA coacervates enhance the understanding of coacervate dynamics, fusion, phase transition mechanisms, and wetting behavior between coacervates, forming a solid foundation for the development of innovative synthetic and programmable coacervates for fundamental studies and applications.

Green Synthesis of CQDs via the Trunks of Bauhinia purpurea as Fluorescence Probes for Rapid and Accurate Detection of Quinoline Yellow.

Carbon quantum dots (CQDs) were greenly synthesized via a single-step hydrothermal method, using the trunks of Bauhinia purpurea as the carbon source. They exhibited good dispersibility, water solubility, high sensitivity, and great stability with a spherical form and a particle size of 2.68 ± 0.32 nm. By utilizing the inner filter effect and dynamic quenching effect, the fluorescence quenching of CQDs can be induced to detect quinoline yellow. Detailed experimental results showed that the change rate of fluorescence intensity of CQDs had a good linear relationship with varying concentrations of quinoline yellow (2-128 µmol/L). It can be clearly observed that the fluorescence quenching occurred within 1 min, its correlation coefficient (R2) is 0.9912, and the detection limit (DL) is 1.7884 µmol/L, substantially lower than the maximum concentration stipulated by the national standard of 209.5 µmol/L. Furthermore, quinoline yellow had been successfully detected in real beverage samples using CQDs, with the recovery rates of 90.6%-110.4% and the relative standard deviation (RSD) ≤ 6.3% and it also showed great anti-interference and selectivity. These findings indicate that the detected quinoline yellow of CQDs possess substantial promise for a wide range of applications within the detected artificial food colors field.

Global, regional and national trends and impacts of natural floods, 1990-2022.

Objective: To assess global, regional and national trends in the impact of floods from 1990 to 2022 and determine factors influencing flood-related deaths. Methods: We used data on flood disasters from the International Disaster Database for 1990-2022 from 168 countries. We calculated the annual percentage change to estimate trends in the rates of people affected and killed by floods by study period, World Health Organization (WHO) region, country income level and flood type. We used multivariable logistic regression analysis to assess the factors associated with death from floods. Findings: From 1990 to 2022, 4713 floods were recorded in 168 countries, which affected > 3.2 billion people, caused 218 353 deaths and were responsible for more than 1.3 trillion United States dollars of economic losses. The WHO Western Pacific Region had the most people affected by floods (> 2.0 billion), accounting for 63.19% (2 024 599 380/3 203 944 965) of all affected populations. The South-East Asia Region had the most deaths (71 713, 32.84%). The African and Eastern Mediterranean Regions had the highest number of people affected and killed by floods per 100 000 population in 2022. The odds of floods causing more than 50 deaths were significantly higher in low-income countries (adjusted odds ratio: 14.34; 95% confidence interval: 7.46 to 30.04) compared with high-income countries. Numbers of people affected and mortality due to floods declined over time. Conclusion: Despite the decreases in populations affected and deaths, floods still have a serious impact on people and economies globally, particularly in lower-income countries. Action is needed to improve disaster risk management and flood mitigation.

Focus on brain-lung crosstalk: Preventing or treating the pathological vicious circle between the brain and the lung.

Recently, there has been increasing attention to bidirectional information exchange between the brain and lungs. Typical physiological data is communicated by channels like the circulation and sympathetic nervous system. However, communication between the brain and lungs can also occur in pathological conditions. Studies have shown that severe traumatic brain injury (TBI), cerebral hemorrhage, subarachnoid hemorrhage (SAH), and other brain diseases can lead to lung damage. Conversely, severe lung diseases such as acute respiratory distress syndrome (ARDS), pneumonia, and respiratory failure can exacerbate neuroinflammatory responses, aggravate brain damage, deteriorate neurological function, and result in poor prognosis. A brain or lung injury can have adverse effects on another organ through various pathways, including inflammation, immunity, oxidative stress, neurosecretory factors, microbiome and oxygen. Researchers have increasingly concentrated on possible links between the brain and lungs. However, there has been little attention given to how the interaction between the brain and lungs affects the development of brain or lung disorders, which can lead to clinical states that are susceptible to alterations and can directly affect treatment results. This review described the relationships between the brain and lung in both physiological and pathological conditions, detailing the various pathways of communication such as neurological, inflammatory, immunological, endocrine, and microbiological pathways. Meanwhile, this review provides a comprehensive summary of both pharmacological and non-pharmacological interventions for diseases related to the brain and lungs. It aims to support clinical endeavors in preventing and treating such ailments and serve as a reference for the development of relevant medications.

Regulating effect of miR-132-3p on the changes of MAPK pathway in rat brains and SH-SY5Y cells exposed to excessive fluoride by targeting expression of MAPK1.

BACKGROUND: Although the changes of mitogen-activated protein kinase (MAPK) pathway in the central nervous system (CNS) induced by excessive fluoride has been confirmed by our previous findings, the underlying mechanism(s) of the action remains unclear. Here, we investigate the possibility that microRNAs (miRNAs) are involved in the aspect. METHODS: As a model of chronic fluorosis, SD rats received different concentrations of fluoride in their drinking water for 3 or 6 months and SH-SY5Y cells were exposed to fluoride. Literature reviews and bioinformatics analyses were used to predict and real-time PCR to measure the expression of 12 miRNAs; an algorithm-based approach was applied to identify multiply potential target-genes and pathways; the dual-luciferase reporter system to detect the association of miR-132-3p with MAPK1; and fluorescence in situ hybridization to detect miR-132-3p localization. The miR-132-3p inhibitor or mimics or MAPK1 silencing RNA were transfected into cultured cells. Expression of protein components of the MAPK pathway was assessed by immunofluorescence or Western blotting. RESULTS: In the rat hippocampus exposed with high fluoride, ten miRNAs were down-regulated and two up-regulated. Among these, miR-132-3p expression was down-regulated to the greatest extent and MAPK1 level (selected from the 220 genes predicted) was corelated with the alteration of miR-132-3p. Furthermore, miR-132-3p level was declined, whereas the protein levels MAPK pathway components were increased in the rat brains and SH-SY5Y cells exposed to high fluoride. MiR-132-3p up-regulated MAPK1 by binding directly to its 3'-untranslated region. Obviously, miR-132-3p mimics or MAPK1 silencing RNA attenuated the elevated expressions of the proteins components of the MAPK pathway induced by fluorosis in SH-SY5Y cells, whereas an inhibitor of miR-132-3p just played the opposite effect. CONCLUSION: MiR-132-3p appears to modulate the changes of MAPK signaling pathway in the CNS associated with chronic fluorosis.

Near-infrared fluorescent probe for sensitive detection and imaging of DNA G4s in living cells.

G-quadruplexs (G4s), four-stranded nucleic acid secondary structures, which formed by guanine-rich sequences play a vital role in human biological systems. Studies have shown that the formation of G4s is closely related to tumor development and apoptosis, which is considered as a new target for the development of anti-tumor drugs. Therefore, it is important to develop novel probes for G4s imaging. In this article, we engineered a near-infrared fluorescent probe (TOH) which can be activated by DNA G4s in living cells and tumor. TOH exhibits high selectivity to the structure of DNA G4s with the limit of detection for DNA G4s (Mito-0.5-2) is calculated to be 0.43 nM. Imaging studies of different cell lines revealed that the brighter fluorescence in cancer cell lines than in normal, indicating that DNA G4s maybe highly express in tumor cell lines. Simultaneously, TOH is also introduced into live tumor tissue imaging and found that the fluorescence intensity of tumor is the brightest relative to normal tissue, further validating the high expression of DNA G4s structures in tumor tissue. These features demonstrate TOH not only have the ability to image DNA G4 structures in real time, but also may have tumor diagnostic capabilities.

Bacterial community analysis of the skin microbiota of cultured Chinese giant salamander infected with Ranavirus.

Skin microorganisms are an important component of host innate immunity and serve as the first line of defense against pathogenic infections. The relative abundance of bacterial species, microbial community assembly, and secretion of specific bacterial metabolites are closely associated with host health. In this study, we investigated the association between the skin microbiome and Ranavirus, and compared the bacterial community assemblage, alpha and beta diversity, and functional predictions of the skin bacterial assemblage in cultured healthy Chinese giant salamanders (Andrias davidianus) and individuals infected with Chinese giant salamander iridovirus (GSIV or ADRV). To achieve this, we employed 16S rRNA amplicon sequencing. The results identified Proteobacteria, Firmicutes, Bacteroidota, and Actinobacteriota as the dominant phyla in the diseased and healthy groups. Alpha diversity analysis indicated that the skin bacterial community in the diseased group exhibited no significant differences in bacterial species diversity and lower species richness compared to the healthy group. Beta diversity suggested that the two group bacterial community was quite different. Kyoto encyclopedia of genes and genomes (KEGG) pathway analyze and clusters of orthologous groups of proteins (COG) function predictions revealed that changes and variations occurred in the metabolic pathways and function distribution of skin bacterial communities in two groups.

Rethinking the potential role of dose painting in personalized ultra-fractionated stereotactic adaptive radiotherapy.

Fractionated radiotherapy was established in the 1920s based upon two principles: (1) delivering daily treatments of equal quantity, unless the clinical situation requires adjustment, and (2) defining a specific treatment period to deliver a total dosage. Modern fractionated radiotherapy continues to adhere to these century-old principles, despite significant advancements in our understanding of radiobiology. At UT Southwestern, we are exploring a novel treatment approach called PULSAR (Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy). This method involves administering tumoricidal doses in a pulse mode with extended intervals, typically spanning weeks or even a month. Extended intervals permit substantial recovery of normal tissues and afford the tumor and tumor microenvironment ample time to undergo significant changes, enabling more meaningful adaptation in response to the evolving characteristics of the tumor. The notion of dose painting in the realm of radiation therapy has long been a subject of contention. The debate primarily revolves around its clinical effectiveness and optimal methods of implementation. In this perspective, we discuss two facets concerning the potential integration of dose painting with PULSAR, along with several practical considerations. If successful, the combination of the two may not only provide another level of personal adaptation ("adaptive dose painting"), but also contribute to the establishment of a timely feedback loop throughout the treatment process. To substantiate our perspective, we conducted a fundamental modeling study focusing on PET-guided dose painting, incorporating tumor heterogeneity and tumor control probability (TCP).

Research progress on venous thrombosis development in patients with malignant tumors.

The coexistence of venous thromboembolism (VTE) within patients with cancer, known as cancer-associated thrombosis (CAT), stands as a prominent cause of mortality in this population. Over recent years, the incidence of VTE has demonstrated a steady increase across diverse tumor types, influenced by several factors such as patient management, tumor-specific risks, and treatment-related aspects. Furthermore, mutations in specific genes have been identified as potential contributors to increased CAT occurrence in particular cancer subtypes. We conducted an extensive review encompassing pivotal historical and ongoing studies on CAT. This review elucidates the risks, mechanisms, reliable markers, and risk assessment methodologies that can significantly guide effective interventions in clinical practice.

Effectiveness of fecal DNA syndecan-2 methylation testing for detection of colorectal cancer in a high-risk Chinese population.

BACKGROUND: Colorectal cancer (CRC) is among the most prevalent and life-threatening malignancies worldwide. Syndecan-2 methylation (mSDC2) testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples. Cancer (CRC) is among the most prevalent and life-threatening malignancies worldwide. mSDC2 testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples. AIM: To validate the effectiveness of fecal DNA mSDC2 testing in the detection of CRC among a high-risk Chinese population to provide evidence-based data for the development of diagnostic and/or screening guidelines for CRC in China. METHODS: A high-risk Chinese cohort consisting of 1130 individuals aged 40-79 years was selected for evaluation via fecal mSDC2 testing. Sensitivity and specificity for CRC, advanced adenoma (AA) and advanced colorectal neoplasia (ACN) were determined. High-risk factors for the incidence of colorectal lesions were determined and a logistic regression model was constructed to reflect the efficacy of the test. RESULTS: A total of 1035 high-risk individuals were included in this study according to established criteria. Among them, 16 suffered from CRC (1.55%), 65 from AA (6.28%) and 189 from non-AAs (18.26%); 150 patients were diagnosed with polyps (14.49%). Diagnoses were established based upon colonoscopic and pathological examinations. Sensitivities of the mSDC2 test for CRC and AA were 87.50% and 40.00%, respectively; specificities were 95.61% for other groups. Positive predictive values of the mSDC2 test for CRC, AA and ACN were 16.09%, 29.89% and 45.98%, respectively; the negative predictive value for CRC was 99.79%. After adjusting for other high-risk covariates, mSDC2 test positivity was found to be a significant risk factor for the occurrence of ACN (P < 0.001). CONCLUSION: Our findings confirmed that offering fecal mSDC2 testing and colonoscopy in combination for CRC screening is effective for earlier detection of malignant colorectal lesions in a high-risk Chinese population.

The relationship between complement C1q and coronary plaque vulnerability based on optical coherence tomography analysis.

To determine the association between complement C1q and vulnerable plaque morphology among coronary artery disease (CAD) patients. We conducted a retrospective observational study of 221 CAD patients admitted to The Second Affiliated Hospital of Xi'an Jiaotong University. Intravascular optical coherence tomography was utilized to describe the culprit plaques' morphology. Using logistic regression analysis to explore the correlation between C1q and vulnerable plaques, and receiver operator characteristic (ROC) analysis assess the predictive accuracy. As reported, the complement C1q level was lower in ACS patients than CCS patients (18.25 ± 3.88 vs. 19.18 ± 4.25, P = 0.045). The low complement-C1q-level group was more prone to develop vulnerable plaques. In lipid-rich plaques, the complement C1q level was positively correlated with the thickness of fibrous cap (r = 0.480, P = 0.041). Univariate and multivariate logistic regression analyses suggested that complement C1q could be an independent contributor to plaques' vulnerability. For plaque rupture, erosion, thrombus, and cholesterol crystals, the areas under the ROC curve of complement C1q level were 0.873, 0.816, 0.785, and 0.837, respectively (P < 0.05 for all). In CAD patients, the complement C1q could be a valuable indicator of plaque vulnerability.

Physical activity improves the visual-spatial working memory of individuals with mild cognitive impairment or Alzheimer's disease: a systematic review and network meta-analysis.

Objective: Our network meta-analysis aimed to ascertain the effect of physical activity on the visual-spatial working memory of individuals with mild cognitive impairment and Alzheimer's disease as well as to propose tailored exercise interventions for each group. Methods: Employing a frequentist approach, we performed a network meta-analysis to compare the effectiveness of different exercise interventions in improving the visual-spatial working memory of individuals with mild cognitive impairment and Alzheimer's disease. Subsequently, we explored the moderating variables influencing the effectiveness of the exercise interventions through a subgroup analysis. Results: We included 34 articles involving 3,074 participants in the meta-analysis, comprised of 1,537 participants from studies on mild cognitive impairment and 1,537 participants from studies on Alzheimer's disease. The articles included exhibited an average quality score of 6.6 (score studies) and 6.75 (reaction time [RT] studies), all passing the inconsistency test (p > 0.05). In the mild cognitive impairment literature, mind-body exercise emerged as the most effective exercise intervention (SMD = 0.61, 95% CI: 0.07-1.14). In Alzheimer's disease research, aerobic exercise was identified as the optimal exercise intervention (SMD = 0.39, 95% CI: 0.06-0.71). Conclusion: The results of the subgroup analysis suggest that the most effective approach to enhancing the visual-spatial working memory of individuals with mild cognitive impairment entails exercising at a frequency of three or more times per week for over 60 min each time and at a moderate intensity for more than 3 months. Suitable exercise options include mind-body exercise, multicomponent exercise, resistance exercise, and aerobic exercise. For individuals with Alzheimer's disease, we recommend moderately intense exercise twice per week for over 90 min per session and for a duration of 3 months or longer, with exercise options encompassing aerobic exercise and resistance exercise.

Effectiveness of BNT162b2 COVID-19 primary series vaccination in children aged 5-17 years in the United States: a cohort study.

BACKGROUND: COVID-19 vaccines are authorized for use in children in the United States; real-world assessment of vaccine effectiveness in children is needed. This study's objective was to estimate the effectiveness of receiving a complete primary series of monovalent BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine in US children. METHODS: This cohort study identified children aged 5-17 years vaccinated with BNT162b2 matched with unvaccinated children. Participants and BNT162b2 vaccinations were identified in Optum and CVS Health insurance administrative claims databases linked with Immunization Information System (IIS) COVID-19 vaccination records from 16 US jurisdictions between December 11, 2020, and May 31, 2022 (end date varied by database and IIS). Vaccinated children were followed from their first BNT162b2 dose and matched to unvaccinated children on calendar date, US county of residence, and demographic and clinical factors. Censoring occurred if vaccinated children failed to receive a timely dose 2 or if unvaccinated children received any dose. Two COVID-19 outcome definitions were evaluated: COVID-19 diagnosis in any medical setting and COVID-19 diagnosis in hospitals/emergency departments (EDs). Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models, and vaccine effectiveness (VE) was estimated as 1 minus HR. VE was estimated overall, within age subgroups, and within variant-specific eras. Sensitivity, negative control, and quantitative bias analyses evaluated various potential biases. RESULTS: There were 453,655 eligible vaccinated children one-to-one matched to unvaccinated comparators (mean age 12 years; 50% female). COVID-19 hospitalizations/ED visits were rare in children, regardless of vaccination status (Optum, 41.2 per 10,000 person-years; CVS Health, 44.1 per 10,000 person-years). Overall, vaccination was associated with reduced incidence of any medically diagnosed COVID-19 (meta-analyzed VE = 38% [95% CI, 36-40%]) and hospital/ED-diagnosed COVID-19 (meta-analyzed VE = 61% [95% CI, 56-65%]). VE estimates were lowest among children 5-11 years and during the Omicron-variant era. CONCLUSIONS: Receipt of a complete BNT162b2 vaccine primary series was associated with overall reduced medically diagnosed COVID-19 and hospital/ED-diagnosed COVID-19 in children; observed VE estimates differed by age group and variant era. REGISTRATION: The study protocol was publicly posted on the BEST Initiative website ( https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf ).

Low socioeconomic status is associated with worse treatment outcomes in patients with Achilles tendinopathy.

OBJECTIVE: To assess whether there is a difference in symptom severity at baseline and 24 weeks follow-up between conservatively managed patients with Achilles tendinopathy (AT) with low socioeconomic status (SES) compared with those with high SES. METHODS: In this prospective cohort study, 200 patients with AT were included and treated according to current guidelines. We linked a neighbourhood SES indicator based on income, employment and education level and divided the patient population into quintiles, with Q1 being the highest SES and Q5 the lowest. Symptom severity at baseline and follow-up was assessed using the Victorian Institute of Sports Assessment-Achilles (VISA-A) score. Treatment adherence was not measured. We used a general linear model and the mean VISA-A scores at baseline and at 6, 12 and 24 weeks follow-up were compared between Q1 (n=45) and Q5 (n=39), while adjusting for age, sex, body mass index (BMI), Ankle Activity Score, symptom duration and baseline VISA-A score. RESULTS: Patients had a median age of 51 years and median BMI of 25.4, 40% were female. 74%, 70% and 58% of the participants completed the VISA-A at 6, 12 and 24 weeks, respectively. VISA-A scores at baseline were similar for Q1 and Q5 (43.9 and 41.8, p=0.591). At 24 weeks, there was a mean (95% CI) difference of 11.2 (1.0 to 21.3, p=0.032) points in favour of Q1 on the VISA-A score. CONCLUSION: AT patients with low SES may have worse outcomes when treated using the current guidelines. The difference in VISA-A score at 24 weeks is larger than the minimal clinically important difference and might be clinically relevant, but comes with uncertainty due to the large dispersion in the data. Clinicians need to consider the impact of social inequality when developing and implementing treatment plans.

MdWRKY71 promotes the susceptibility of apple to Glomerella leaf spot by controlling salicylic acid degradation.

Glomerella leaf spot (GLS), a fungal disease caused by Colletotrichum fructicola, severely affects apple (Malus domestica) quality and yield. In this study, we found that the transcription factor MdWRKY71 was significantly induced by C. fructicola infection in the GLS-susceptible apple cultivar Royal Gala. The overexpression of MdWRKY71 in apple leaves resulted in increased susceptibility to C. fructicola, whereas RNA interference of MdWRKY71 in leaves showed the opposite phenotypes. These findings suggest that MdWRKY71 functions as a susceptibility factor for the apple-C. fructicola interaction. Furthermore, MdWRKY71 directly bound to the promoter of the salicylic acid (SA) degradation gene Downy Mildew Resistant 6 (DMR6)-Like Oxygenase 1 (DLO1) and promoted its expression, resulting in a reduced SA level. The sensitivity of 35S:MdWRKY71 leaves to C. fructicola can be effectively alleviated by knocking down MdDLO1 expression, confirming the critical role of MdWRKY71-mediated SA degradation via regulating MdDLO1 expression in GLS susceptibility. In summary, we identified a GLS susceptibility factor, MdWRKY71, that targets the apple SA degradation pathway to promote fungal infection.