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1.
J Dent ; 148: 105214, 2024 Jun 29.
Article in English | MEDLINE | ID: mdl-38950767

ABSTRACT

OBJECTIVES: To evaluate the mechanical properties of root canal dentin treated with sodium hypochlorite (NaOCl) in combination with hydroxyethylidene diphosphonic acid (HEDP) or ethylenediaminetetraacetic acid (EDTA). METHODS: For testing fracture resistance, 45 single-rooted teeth were instrumented and irrigated with NaOCl/HEDP, NaOCl/EDTA, or distilled water. Fifteen untreated teeth served as control. After obturation, specimens from the experimental groups were thermocycled, dynamically-loaded, and then statically-loaded in a universal testing machine until failure. For flexural strength analysis, 15 teeth were instrumented and irrigated with NaOCl/HEDP or NaOCl/EDTA. Root segments were sectioned into dentin bars and tested for flexural strength using a universal testing machine. For microhardness evaluation, 20 teeth were instrumented and irrigated with NaOCl/HEDP or NaOCl/EDTA. Dentin disks from the coronal-third of each root segment were prepared, one before and one after irrigation, for microhardness testing with a Knoop hardness tester. RESULTS: The highest fracture resistance was recorded in the untreated group, and the lowest in the EDTA group. Although the HEDP group had higher fracture resistance than the EDTA group, the distilled water group demonstrated even greater fracture resistance than the HEDP group. Specimens treated with HEDP had significantly higher flexural strength and microhardness values when compared with those treated with EDTA. CONCLUSION: The fracture resistance, flexural strength, and microhardness of root canal dentin were higher when root canals were irrigated with NaOCl/HEDP, when compared with NaOCl/EDTA. CLINICAL SIGNIFICANCE: Irrigating root canals with NaOCl combined with HEDP significantly improves the mechanical integrity of root canal dentin compared to the use of NaOCl with EDTA.

2.
Compr Rev Food Sci Food Saf ; 23(4): e13361, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39031723

ABSTRACT

The development of future food is devoted not only to obtaining a sustainable food supply but also to providing high-quality foods for humans. Plant-derived non-starch polysaccharides (PNPs) are widely available, biocompatible, and nontoxic and have been largely applied to the food industry owing to their mechanical properties and biological activities. PNPs are considered excellent biomaterials and food ingredients contributing to future food development. However, a comprehensive review of the potential applications of PNPs in future food has not been reported. This review summarized the physicochemical and biological activities of PNPs and then discussed the structure-activity relationships of PNPs. Latest studies of PNPs on future foods including cell-cultured meat, food for special medical purposes (FSMPs), and three-dimensional-printed foods were reviewed. The challenges and prospects of PNPs applied to future food were critically proposed. PNPs with strong thermal stability are considered good thickeners, emulsifiers, and gelatinizers that greatly improve the processing adaptability of foods. The mechanical properties of PNPs and decellularized plant-based PNPs make them desirable scaffolds for cultured meat manufacturing. In addition, the biological activities of PNPs exhibit multiple health-promoting effects; therefore, PNPs can act as food ingredients producing FSMP to promote human health. Three-dimensional printing technology enhances food structures and biological activities of functional foods, which is in favor of expanding the application scopes of PNPs in future food. PNPs are promising in future food manufacturing, and more efforts need to be made to realize their commercial applications.


Subject(s)
Polysaccharides , Polysaccharides/chemistry , Humans , Plants/chemistry
3.
Article in English | MEDLINE | ID: mdl-38980942

ABSTRACT

Intelligent colorimetric freshness indicator is a low-cost way to intuitively monitor the freshness of fresh food. A colorimetric strip sensor array was prepared by p-dimethylaminocinnamaldehyde (PDL)-doped poly(vinyl alcohol) (PVA) and chitosan (Chit) for the quantitative analysis of indole, which is an indicator of shrimp freshness. As a result of indole simulation, the array strip turned from faint yellow to pink or mulberry color with the increasing indole concentration, like a progress bar. The indicator film exhibited excellent permeability, mechanical and thermal stability, and color responsiveness to indole, which was attributed to the interactions between PDL and Chit/PVA. Furthermore, the colorimetric strip sensor array provided a good relationship between the indole concentration and the color intensity within a range of 50-350 ppb. The pathogens and spoilage bacteria of shrimp possessed the ability to produce indole, which caused the color changes of the strip sensor array. In the shrimp freshness monitoring experiment, the color-changing progress of the strip sensor array was in agreement with the simulation and could distinguish the shrimp freshness levels. The image classification system based on deep learning were developed, the accuracies of four DCNN algorithms are above 90%, with VGG16 achieving the highest accuracy at 97.89%. Consequently, a "progress bar" strip sensor array has the potential to realize nondestructive, more precise, and commercially available food freshness monitoring using simple visual inspection and intelligent equipment identification.

4.
Popul Dev Rev ; 50(2): 403-436, 2024 Jun.
Article in English | MEDLINE | ID: mdl-39035023

ABSTRACT

The disparity in life expectancy between white and black Americans exceeds five years for men and three years for women. While prior research has investigated the roles of healthcare, health behaviors, biological risk, socioeconomic status, and life course effects on black mortality, the literature on the geographic origins of the gap is more limited. This study examines how the black-white life expectancy gap varies across counties and how much of the national gap is attributable to within-county racial inequality versus differences between counties. The estimates suggest that over 90% of the national gap can be attributed to within-county factors. Using a quasi-experimental research design, I find that black-white residential segregation increases the gap by approximately 16 years for men and five years for women. The segregation effect loads heavily on causes of death associated with access to and quality of healthcare; safety and violence; and public health measures. Residential segregation does not appear to operate through health behaviors or individual-level factors, but instead acts primarily through institutional mechanisms. Efforts to address racial disparities in mortality should focus on reducing racial residential segregation or reducing inequalities in the mechanisms through which residential segregation acts: public services, employment opportunities, and community resources.

6.
Foods ; 13(11)2024 May 25.
Article in English | MEDLINE | ID: mdl-38890891

ABSTRACT

The quality of fresh foods tends to deteriorate rapidly during harvesting, storage, and transportation. Intelligent detection equipment is designed to monitor and ensure product quality in the supply chain, measure appropriate food quality parameters in real time, and thus minimize quality degradation and potential financial losses. Through various available tracking devices, consumers can obtain actionable information about fresh food products. This paper reviews the recent progress in intelligent detection equipment for sensing the quality deterioration of fresh foods, including computer vision equipment, electronic nose, smart colorimetric films, hyperspectral imaging (HSI), near-infrared spectroscopy (NIR), nuclear magnetic resonance (NMR), ultrasonic non-destructive testing, and intelligent tracing equipment. These devices offer the advantages of high speed, non-destructive operation, precision, and high sensitivity.

7.
Theor Appl Genet ; 137(5): 117, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38700534

ABSTRACT

KEY MESSAGE: A large-effect QTL was fine mapped, which revealed 79 gene models, with 10 promising candidate genes, along with a novel inversion. In commercial maize breeding, doubled haploid (DH) technology is arguably the most efficient resource for rapidly developing novel, completely homozygous lines. However, the DH strategy, using in vivo haploid induction, currently requires the use of mutagenic agents which can be not only hazardous, but laborious. This study focuses on an alternative approach to develop DH lines-spontaneous haploid genome duplication (SHGD) via naturally restored haploid male fertility (HMF). Inbred lines A427 and Wf9, the former with high HMF and the latter with low HMF, were selected to fine-map a large-effect QTL associated with SHGD-qshgd1. SHGD alleles were derived from A427, with novel haploid recombinant groups having varying levels of the A427 chromosomal region recovered. The chromosomal region of interest is composed of 45 megabases (Mb) of genetic information on chromosome 5. Significant differences between haploid recombinant groups for HMF were identified, signaling the possibility of mapping the QTL more closely. Due to suppression of recombination from the proximity of the centromere, and a newly discovered inversion region, the associated QTL was only confined to a 25 Mb region, within which only a single recombinant was observed among ca. 9,000 BC1 individuals. Nevertheless, 79 gene models were identified within this 25 Mb region. Additionally, 10 promising candidate genes, based on RNA-seq data, are described for future evaluation, while the narrowed down genome region is accessible for straightforward introgression into elite germplasm by BC methods.


Subject(s)
Chromosome Mapping , Haploidy , Quantitative Trait Loci , Zea mays , Zea mays/genetics , Chromosome Mapping/methods , Plant Breeding , Genome, Plant , Phenotype , Alleles , Chromosomes, Plant/genetics , Genes, Plant
9.
Food Chem ; 453: 139713, 2024 Sep 30.
Article in English | MEDLINE | ID: mdl-38772307

ABSTRACT

Due to their high water content, frozen mushrooms (Agaricus bisporus) were greatly affected by ice crystal formation, which can lead to the destruction of tissue structure, serious browning, high juice loss, and difficulty in maintaining good sensory characteristics. In order to improve the quality of frozen Agaricus bisporus, this study employed Artificial neural network and genetic algorithm (ANN-GA) to optimize the amount of composite color protectant, and identified the optimal freezing conditions for freezing Agaricus bisporus by determining the freezing curves under different magnetic field-assisted freezing conditions, the color variance, texture and structure, drip loss, and distribution of moisture. Furthering, using X-ray µCT three dimensional images were taken to characterize the microstructure of the samples. Among them, the 6 mT magnetic field-assisted freezing treatment group was significantly better than the control group, and the results showed that the magnetic field-assisted freezing combined with chemical color protectant as a composite processing technology improved the quality of frozen Agaricus bisporus. This provides a theoretical basis and technical support for enhanced processing of frozen Agaricus bisporus.


Subject(s)
Agaricus , Freezing , Magnetic Fields , Agaricus/chemistry , Agaricus/radiation effects , Color , Neural Networks, Computer , Food Preservation/methods , Food Preservation/instrumentation , Algorithms
10.
Indian J Otolaryngol Head Neck Surg ; 76(2): 2166-2170, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38566724

ABSTRACT

Perioperative high dose rate brachytherapy involves insertion of brachytherapy catheter over the tumor bed during surgical removal of disease followed by radiation in the postoperative period. It has applications in radiotherapy dose escalation or reirradiation and for extending the surgical margins. We report here initial results of treatment in five cases of locally advanced head and neck cancers.

11.
PLoS One ; 19(4): e0297469, 2024.
Article in English | MEDLINE | ID: mdl-38626063

ABSTRACT

Cardiopulmonary and renal end organ (CPR) complications are associated with early mortality among individuals with sickle cell disease (SCD). However, there is limited knowledge regarding acute care utilization for individuals with SCD and CPR complications. Our objective was to determine the prevalence of CPR complications in a state specific SCD population and compare acute care utilization among individuals with and without CPR complications. We leveraged 2017-2020 data for individuals with SCD identified by the Sickle Cell Data Collection program in Wisconsin. The prevalence of CPR complications is determined for distinct age groups. Generalized linear models adjusted for age compared the rate of acute care visits/person/year among individuals who had cardiopulmonary only, renal only, both cardiopulmonary and renal, or no CPR complications. There were 1378 individuals with SCD, 52% females, mean (SD) age 28.3 (18.5) years; 48% had at least one CPR complication during the study period. The prevalence of CPR complications was higher in adults (69%) compared to pediatric (15%) and transition (51%) groups. Individuals with SCD and cardiopulmonary complications had higher acute visit rates than those without CPR complications (5.4 (IQR 5.0-5.8) vs 2.4 (IQR 2.1-2.5), p <0.001)). Acute care visit rates were similar between individuals with SCD who had renal only complications and no CPR complications (2.7 (IQR 2.5-3.0) vs 2.4 (2.1-2.5), p = 0.24). The high acute care visit rates, especially for those with cardiopulmonary complications, warrant further investigation to understand risk factors for CPR complications, the underlying reasons and identify effective disease management strategies.


Subject(s)
Anemia, Sickle Cell , Adult , Female , Humans , Child , Male , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/therapy , Anemia, Sickle Cell/epidemiology , Kidney , Disease Management , Wisconsin , Critical Care
12.
J Theor Biol ; 587: 111824, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38604595

ABSTRACT

The human gut microbiota relies on complex carbohydrates (glycans) for energy and growth, primarily dietary fiber and host-derived mucins. We introduce a mathematical model of a glycan generalist and a mucin specialist in a two-compartment chemostat model of the human colon. Our objective is to characterize the influence of dietary fiber and mucin supply on the abundance of mucin-degrading species within the gut ecosystem. Current mathematical gut reactor models that include the enzymatic degradation of glycans do not differentiate between glycan types and their degraders. The model we present distinguishes between a generalist that can degrade both dietary fiber and mucin, and a specialist species that can only degrade mucin. The integrity of the colonic mucus barrier is essential for overall human health and well-being, with the mucin specialist Akkermanisa muciniphila being associated with a healthy mucus layer. Competition, particularly between the specialist and generalists like Bacteroides thetaiotaomicron, may lead to mucus layer erosion, especially during periods of dietary fiber deprivation. Our model treats the colon as a gut reactor system, dividing it into two compartments that represent the lumen and the mucus of the gut, resulting in a complex system of ordinary differential equations with a large and uncertain parameter space. To understand the influence of model parameters on long-term behavior, we employ a random forest classifier, a supervised machine learning method. Additionally, a variance-based sensitivity analysis is utilized to determine the sensitivity of steady-state values to changes in model parameter inputs. By constructing this model, we can investigate the underlying mechanisms that control gut microbiota composition and function, free from confounding factors.


Subject(s)
Dietary Fiber , Gastrointestinal Microbiome , Models, Biological , Mucins , Mucus , Mucins/metabolism , Dietary Fiber/metabolism , Humans , Gastrointestinal Microbiome/physiology , Mucus/metabolism , Colon/metabolism , Colon/microbiology , Polysaccharides/metabolism
13.
Lancet Reg Health Southeast Asia ; 24: 100392, 2024 May.
Article in English | MEDLINE | ID: mdl-38550605

ABSTRACT

Background: Globally, most of the randomised trials with hypofractionation in patients with breast cancer have used 3-dimensional conformal radiotherapy technique (3D-CRT). As facilities for 3D-CRT technique may not be available in low-resource settings, there is a need to see if hypofractionation is feasible and safe with 2-dimensional (2-D) technique. In this study, we compared a 3-week radiation schedule with a 2-week schedule of hypofractionated radiotherapy in patients with breast cancer with 2-D technique. Methods: The current study was an open-label, randomised, phase 3 trial. Patients with breast cancer, stage I-III, post mastectomy or after breast conservative surgery who needed adjuvant locoregional radiotherapy were randomised in the Department of Radiotherapy & Oncology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India; to 34Gy in 10 fractions over 2 weeks (2-week arm) or 35Gy in 15 fractions over 3 weeks to the chest wall and 40Gy/15#/3wks to breast and supraclavicular fossa (3-week arm). Boost dose when indicated was 8-10Gy/2-4#/2-4 days in both the arms. Patients were planned on a 2-dimensional (2D) simulator with 2 tangential fields to breast/chest wall and incident supraclavicular fossa field. Acute toxicity was assessed using the Radiation Therapy Oncology Group (RTOG) grading scale. Assessments were carried out weekly during radiotherapy and at 4 weeks after treatment by the physician. Cosmetic outcome was assessed using the Harvard/National Surgical Adjuvant Breast and Bowel Project (NSABP)/RTOG scale. The toxicity rates between the two arms were compared using Fisher's exact tests. The trial was approved by institutional ethics committee and registered with ClinicalTrials.gov, number NCT04075058. Findings: This study included 1121 eligible patients from June 2015 to December 2020. Median follow-up was 35 months (6-84 months). Mean age was 48 years (24-75 years). The patient characteristics were comparable between the two arms except for more mastectomies in the 3-week arm and more node-positive patients in the 2-week arm. There were more oestrogen receptor-positive tumors in the 3-week arm. Acute skin toxicities were comparable between the two arms. Grade 2 and 3 skin toxicity was 100 (18%) and 82 (15%); and 16 (3%) and 12 (2%) in the 3-week and 2-week arm (p = 0.21), respectively. Cosmetic outcome was assessed as Excellent or Good for 89% of patients in the 3-week arm as compared to 94% in the 2-week arm (p = 0.004). Interpretation: The two radiation schedules were comparable in terms of acute skin toxicity. The cosmetic outcome was better with the 2-week schedule. The preliminary findings indicate 2-week radiotherapy schedule with 2-D technique was better than the 3-week schedule in patients with breast cancer. However, disease outcomes and late-term toxicities need to be further checked. Funding: This study was funded by Science and Engineering Research Board (SERB), India.

14.
J Orthop ; 52: 107-111, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38440411

ABSTRACT

Background: Robotic-assisted total knee replacement (RA-TKR) is a significant advancement in orthopedic surgery, but intra-operative decision-making remains challenging. Pre-operative imaging techniques, particularly CT scans, have gained momentum, providing insights into the patient's anatomy, improving implant positioning and alignment. However, further research is needed to explore their influence on RA-TKR planning and execution. Materials and methods: The hospital based cross-sectional study was conducted in Orthopedics department of Sparsh Speciality Hospital, Bangalore & Sunshine Hospital, Hyderabad. A total of 1020 participants in the age group over 50 years during the study period were included based on convenient sampling. The axial CT images were taken preoperatively and RA-TKA was done for all the patients. Results: The study participant's average age was 64.01 ± 7.13. Out of 1020 patients 259 (24.4%) were males and 761 (74.6%) were females. The median femoral, tibia and Polyethylene predicted and the actual component were same with the side of surgery and BMI. The median femoral predicted actual component was significantly higher among the age category of more than 80 years when compared to other age groups. The median femoral, tibia and Polyethylene predicted was higher in males when compared to females. Conclusion: Pre-operative CT scans enhance RA-TKR procedures by providing precise anatomical insights, enhancing implant placement, and identifying potential issues, improving surgical outcomes and patient satisfaction.

15.
Int J Biol Macromol ; 264(Pt 2): 130629, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38453112

ABSTRACT

Elderly people often experience difficulty in swallowing and have impaired regulation of the nervous system. Furthermore, their blood glucose level can rise easily after eating. Therefore, functional foods that are easy to swallow and can maintain blood glucose at a lower level have been an important research topic in recent years. In this study, 3D printing was combined with dry heating to modify the starch in white quinoa and brown rice to develop whole grain foods with Osmanthus flavor that meet the dietary habits of the elderly. The samples were tested for printability, swallowing performance, and in vitro digestion. The results showed that after dry heating, all samples had shear-thinning properties and could pass through the extrusion nozzle of the printer smoothly. Both white quinoa and brown rice showed improved printability and self-support compared to the control. B45 (white quinoa, dry heating for 45 min) and C45 (brown rice, dry heating for 45 min) had significant elasticity and greater internal interaction strength during swallowing to resist disintegration of food particles during chewing. B45, C30, and C45, conformed to class 4 consistency and were characterized by easy swallowing of the diet. Further, dry heating resulted in greater resistance to enzymatic degradation of white quinoa and brown rice starch, with overall in vitro digestibility lower than the control.


Subject(s)
Diabetes Mellitus , Oryza , Humans , Aged , Starch/chemistry , Blood Glucose/metabolism , Heating , Digestion , Printing, Three-Dimensional , Oryza/chemistry
16.
J Cancer Res Ther ; 20(1): 71-78, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-38554301

ABSTRACT

INTRODUCTION: Linear accelerator (LINAC) embedded with kV source-imager system is capable to do image-guided radiotherapy. The only disadvantage of cone-beam computed tomography image acquisition during treatment is the extra radiation dose to the patient. The aim of this study is to optimize the CBCT imaging doses likely to be received by the patient undergoing radiotherapy without affecting image quality. MATERIAL AND METHODS: The imaging dose to the patient was estimated on CTDI phantoms. The effect of additional filters of different materials (copper, brass, aluminum of thickness 0.1 mm each) was evaluated to find the optimized dose imaging technique. For the pelvis, a single imaging protocol available on the machine was used, whereas for the head and neck region, two protocols, high-quality head and standard-dose head were used. The image quality was assessed on CATPHAN-504 phantom using Owl CATPHAN® QA online tool. A new term "Image Assessment score" (IAS) was introduced to evaluate the image quality. RESULT: In the pelvis protocol, CBCT imaging doses with an additional 0.1-mm brass, copper, and aluminum filter were measured to be reduced by 7.1%, 4.7%, and 2.5%, respectively, whereas for high-quality head protocol, the dose reduction was 25.4% (with brass filter), 22% (with copper filter), and 3.1% (with aluminum filter). For the standard-dose head protocol, doses were reduced by 7.5%, 2.8%, and 2.1% with additional 0.1-mm brass copper and aluminum filters, respectively. Acceptable image quality was observed with all the filters. CONCLUSION: Although the reconstructed images were found somewhat noisier, they did not affect the purpose of imaging, that is, treatment position verification. It was observed that these extra filters further reduce the imaging dose without much affecting the image quality.


Subject(s)
Copper , Spiral Cone-Beam Computed Tomography , Zinc , Humans , Aluminum , Cone-Beam Computed Tomography/methods , Phantoms, Imaging
17.
J Cancer Res Ther ; 20(1): 389-395, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-38554351

ABSTRACT

INTRODUCTION: Total skin electron beam therapy, commonly known as TSET, is a good choice of treatment for patients suffering from mycosis fungoides. The aim of this study was to introduce a new approach to the beam profile measurement using diodes and to calculate the monitor units required for the TSET treatment by the use of a simple setup of output measurement. Dosimetric measurements required for the treatment were taken to establish the Stanford technique in the department, and the measured data was compared with the published data. MATERIALS AND METHODS: High-energy Linear Accelerator Clinac-DHX, Varian medical system, Palo Alto, CA, was commissioned for TSET. The output of the machine was measured by the use of a Parallel-Plate Chamber (PPC40) as per the TRS 398 recommendation. Diode dosimeters (EDD2 and EDD5) were used for beam profile measurements due to easy setup and to reduce the measurement time. RESULTS: Homogeneous dose distribution within a field size of 80 cm x160 cm was observed with the variation of -5.0% on the horizontal axis and -5.4% on the vertical axis. The calculated monitor unit to deliver 200 cGy per fraction per field at the source to surface (SSD) of 416 cm was 489 MU. CONCLUSION: The technique described for the output measurements is simple and accurate. Results of the absorbed dose and MU measured were within good agreement compared to the published literature.


Subject(s)
Particle Accelerators , Radiometry , Humans , Radiotherapy Dosage , Radiometry/methods
18.
Int J Antimicrob Agents ; 63(5): 107125, 2024 May.
Article in English | MEDLINE | ID: mdl-38431109

ABSTRACT

RATIONALE AND OBJECTIVES: ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) constitute a threat to humans worldwide. India is now the most populous country. The goal was to investigate the evolution of the rates of antimicrobial resistance in ESKAPE pathogens across India over the 2010-20 decade. METHODS: The data (89 studies) were retrieved from the Medline PubMed repository using specific keywords. RESULTS: The study of 20 177 ESKAPE isolates showed that A. baumannii isolates were the most represented (35.9%, n = 7238), followed by P. aeruginosa (25.3%, n = 5113), K. pneumoniae (19.5%, n = 3934), S. aureus (16.3%, n = 3286), E. faecium (2.6%, n = 517) and Enterobacter spp. (0.4%, n = 89). A notable increase in the resistance rates to antimicrobial agents occurred over the 2010-20 decade. The most important levels of resistance were observed in 2016-20 for A. baumannii (90% of resistance to the amoxicillin-clavulanate combination) and K. pneumoniae (81.6% of resistance to gentamycin). The rise in ß-lactamase activities was correlated with an increase in the positivity of Gram-negative isolates for ß-lactamase genes. CONCLUSIONS: This review highlighted that, in contrast to developed countries that kept resistance levels under control, a considerable increase in resistance to various classes of antibiotics occurred in ESKAPE pathogens in India over the 2010-2020 decade.


Subject(s)
Acinetobacter baumannii , Anti-Bacterial Agents , Klebsiella pneumoniae , India/epidemiology , Humans , Anti-Bacterial Agents/pharmacology , Acinetobacter baumannii/drug effects , Acinetobacter baumannii/genetics , Acinetobacter baumannii/isolation & purification , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/isolation & purification , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/isolation & purification , Drug Resistance, Bacterial , Staphylococcus aureus/drug effects , Staphylococcus aureus/genetics , Staphylococcus aureus/isolation & purification , Enterococcus faecium/drug effects , Enterococcus faecium/genetics , Enterococcus faecium/isolation & purification , Drug Resistance, Multiple, Bacterial/genetics , Enterobacter/drug effects , Enterobacter/genetics , Enterobacter/isolation & purification
19.
Cell Metab ; 36(2): 224-228, 2024 02 06.
Article in English | MEDLINE | ID: mdl-38325335

ABSTRACT

Cardiometabolic disease is a leading cause of death and plays a key role in recent life expectancy trends worldwide. We highlight inequalities in cardiometabolic disease mortality across sex, race/ethnicity, geographic region, and urbanicity within the United States, as well as across high-income countries.


Subject(s)
Cardiovascular Diseases , Life Expectancy , Humans , United States/epidemiology , Developed Countries , Ethnicity
20.
bioRxiv ; 2024 Jan 26.
Article in English | MEDLINE | ID: mdl-38328097

ABSTRACT

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based viral breakthrough assays identified the HIV-1(Y99H/A128T IN) variant that confers substantial resistance to this inhibitor. Here, we have elucidated the unexpected mechanism of viral resistance to PIR. While both Tyr99 and Ala128 are positioned within the inhibitor binding V-shaped cavity at the IN catalytic core domain (CCD) dimer interface, the Y99H/A128T IN mutations did not substantially affect direct binding of PIR to the CCD dimer or functional oligomerization of full-length IN. Instead, the drug-resistant mutations introduced a steric hindrance at the inhibitor mediated interface between CCD and C-terminal domain (CTD) and compromised CTD binding to the CCDY99H/A128T + PIR complex. Consequently, full-length INY99H/A128T was substantially less susceptible to the PIR induced hyper-multimerization than the WT protein, and HIV-1(Y99H/A128T IN) conferred >150-fold resistance to the inhibitor compared to the WT virus. By rationally modifying PIR we have developed its analog EKC110, which readily induced hyper-multimerization of INY99H/A128T in vitro and was ~14-fold more potent against HIV-1(Y99H/A128T IN) than the parent inhibitor. These findings suggest a path for developing improved PIR chemotypes with a higher barrier to resistance for their potential clinical use.

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