Comparative Anatomy of the Dentate Mossy Cells in Nonhuman Primates: Their Spatial Distributions and Axonal Projections Compared With Mouse Mossy Cells.

Glutamatergic mossy cells (MCs) mediate associational and commissural connectivity, exhibiting significant heterogeneity along the septotemporal axis of the mouse dentate gyrus (DG). However, it remains unclear whether the neuronal features of MCs are conserved across mammals. This study compares the neuroanatomy of MCs in the DG of mice and monkeys. The MC marker, calretinin, distinguishes two subpopulations: septal and temporal. Dual-colored fluorescence labeling is utilized to compare the axonal projection patterns of these subpopulations. In both mice and monkeys, septal and temporal MCs project axons across the longitudinal axis of the ipsilateral DG, indicating conserved associational projections. However, unlike in mice, no MC subpopulations in monkeys make commissural projections to the contralateral DG. In monkeys, temporal MCs send associational fibers exclusively to the inner molecular layer, while septal MCs give rise to wide axonal projections spanning multiple molecular layers, akin to equivalent MC subpopulations in mice. Despite conserved septotemporal heterogeneity, interspecies differences are observed in the topological organization of septal MCs, particularly in the relative axonal density in each molecular layer along the septotemporal axis of the DG. In summary, this comparative analysis sheds light on both conserved and divergent features of MCs in the DG of mice and monkeys. These findings have implications for understanding functional differentiation along the septotemporal axis of the DG and contribute to our knowledge of the anatomical evolution of the DG circuit in mammals.

Causal effect of age first had sexual intercourse and lifetime number of sexual partners on cervical cancer.

Objective: In this study, we aimed to investigate whether age first had sexual intercourse (AFSI) and lifetime number of sexual partners (LNSP) have a direct causal effect on cervical cancer by Mendelian randomization (MR) analysis. Methods: Four approaches were used for MR Analysis, including MR-Egger, weighted method, weighted median, and inverse variance weighted (IVW). MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) as well as MR-Egger regression analysis were conducted to detect whether there was pleiotropy between IVs and outcome, and the outlier SNPs can be detected by MR-PRESSO. The presence or absence of heterogeneity among IVs was suggested according to Cochran's Q statistic. Leave-one-out sensitivity analysis was performed to identify and remove SNPs which could independently change the results. We corrected the results using Bonferroni correction. Results: From the results of IVW, AFSI had a negative effect on cervical cancer (OR = 0.996, 95 % CI: 0.995, 0.998 P = 1.70E-07), which still persisted after Bonferroni correction. However, no causal effect of LNSP on cervical cancer was found according to the IVW results (OR = 1.003, 95 % CI: 1.000, 1.007, P = 0.071). From the results of MR-PRESSO and MR-Egger, no SNP with horizontal pleiotropy between cervical cancer was detected and no SNP was identified as an outlier SNP. Cochran's Q statistic suggested that no heterogeneity existed among IVs of AFSI and LNSP. According to Leave-one-out analysis, the results of MR did not change after excluding any single IV. Conclusion: This MR study reveals that early AFSI has a causal effect on cervical cancer.

Disparities in Rates of Death From HIV or Tuberculosis Before Age 65 Years, by Race, Ethnicity, and Sex, United States, 2011-2020.

OBJECTIVE: Death from tuberculosis or HIV among people from racial and ethnic minority groups who are aged <65 years is a public health concern. We describe age-adjusted, absolute, and relative death rates from HIV or tuberculosis from 2011 through 2020 by sex, race, and ethnicity among US residents. METHODS: We used mortality data from the Centers for Disease Control and Prevention online data system on deaths from multiple causes from 2011 through 2020 to calculate age-adjusted death rates and absolute and relative disparities in rates of death by sex, race, and ethnicity. We calculated corresponding 95% CIs for all rates and determined significance at P < .05 by using z tests. RESULTS: For tuberculosis, when compared with non-Hispanic White residents, non-Hispanic American Indian or Alaska Native residents had the highest level of disparity in rate of death (666.7%). Similarly, as compared with non-Hispanic White female residents, American Indian or Alaska Native female residents had a high relative disparity in death from tuberculosis (620.0%). For HIV, the age-adjusted death rate was more than 8 times higher among non-Hispanic Black residents than among non-Hispanic White residents, and the relative disparity was 735.1%. When compared with non-Hispanic White female residents, Black female residents had a high relative disparity in death from HIV (1529.2%). CONCLUSION: Large disparities in rates of death from tuberculosis or HIV among US residents aged <65 years based on sex, race, and ethnicity indicate an ongoing unmet need for effective interventions. Intervention strategies are needed to address disparities in rates of death and infection among racial and ethnic minority populations.

Comparison of Light-Sheet Fluorescence Microscopy and Fast-Confocal Microscopy for Three-Dimensional Imaging of Cleared Mouse Brain.

Whole-brain imaging is important for understanding brain functions through deciphering tissue structures, neuronal circuits, and single-neuron tracing. Thus, many clearing methods have been developed to acquire whole-brain images or images of three-dimensional thick tissues. However, there are several limitations to imaging whole-brain volumes, including long image acquisition times, large volumes of data, and a long post-image process. Based on these limitations, many researchers are unsure about which light microscopy is most suitable for imaging thick tissues. Here, we compared fast-confocal microscopy with light-sheet fluorescence microscopy for whole-brain three-dimensional imaging, which can acquire images the fastest. To compare the two types of microscopies for large-volume imaging, we performed tissue clearing of a whole mouse brain, and changed the sample chamber and low- magnification objective lens and modified the sample holder of a light-sheet fluorescence microscope. We found out that light-sheet fluorescence microscopy using a 2.5× objective lens possesses several advantages, including saving time, large-volume image acquisitions, and high Z-resolution, over fast-confocal microscopy, which uses a 4× objective lens. Therefore, we suggest that light-sheet fluorescence microscopy is suitable for whole mouse brain imaging and for obtaining high-resolution three-dimensional images.

Pivotal Role of Slitrk1 in Adult Striatal Cholinergic Neurons in Mice: Implication in Tourette Syndrome.

OBJECTIVE: The SLIT and NTRK-like 1 (SLITRK1) gene mutation and striatal cholinergic interneurons (ChIs) loss are associated with Tourette syndrome (TS). ChIs comprise only 1 to 2% of striatal neurons but project widely throughout the stratum to impact various striatal neurotransmission, including TS-related dopaminergic transmission. Here, we link striatal Slitrk1, ChI function, and dopaminergic transmission and their associations with TS-like tic behaviors. METHODS: Slitrk1-KD mice were induced by bilaterally injecting Slitrk1 siRNA into their dorsal striatum. Control mice received scrambled siRNA injection. Their TS-like tic behaviors, prepulse inhibition, sensory-motor function and dopamine-related behaviors were compared. We also compared dopamine and ACh levels in microdialysates, Slitrk protein and dopamine transporter levels, and numbers of Slitrk-positive ChIs and activated ChIs in the striatum between two mouse groups, and electrophysiological properties between Slitrk-positive and Slitrk-negative striatal ChIs. RESULTS: Slitrk1-KD mice exhibit TS-like haloperidol-sensitive stereotypic tic behaviors, impaired prepulse inhibition, and delayed sensorimotor response compared with the control group. These TS-like characteristics correlate with lower striatal Slitrk1 protein levels, fewer Slitrk1-containing ChIs, and fewer activated ChIs in Slitrk1-KD mice. Based on their electrophysiological properties, Slitrk1-negative ChIs are less excitable than Slitrk1-positive ChIs. Slitrk1-KD mice have lower evoked acetylcholine and dopamine levels, higher tonic dopamine levels, and downregulated dopamine transporters in the striatum, increased apomorphine-induced climbing behaviors, and impaired methamphetamine-induced hyperlocomotion compared with controls. INTERPRETATION: Slitrk1 is pivotal in maintaining striatal ChIs activity and subsequent dopaminergic transmission for normal motor functioning. Furthermore, conditional striatal Slitrk1-KD mice may serve as a translational modality with aspects of TS phenomenology. ANN NEUROL 2023.

A Rare Complication of Henoch-Schönlein Purpura/IgA Vasculitis in an Adult Woman After COVID-19 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can affect multiple organs due to activation of an inflammatory response. One of the key components of this response is the activation of immunoglobulin A (IgA), thus causing endothelial injury and inflammation. Henoch-Schönlein purpura (HSP) has been rarely reported in adult patients as a complication of the coronavirus disease 2019 (COVID-19) infection. In this report, we present a case of HSP occurring one week after the diagnosis of COVID-19 in a 23-year-old woman. Her symptoms included nausea, vomiting, diffused abdominal pain, joint pain, hematuria, and palpable purpura of the lower extremities. She was treated with intravenous methylprednisolone sodium succinate, followed by oral prednisone therapy, which resulted in clinical improvement, including resolution of abdominal and joint pain as well as skin rashes, without remaining renal complication.

Pancreatic Stellate Cells and the Targeted Therapeutic Strategies in Chronic Pancreatitis.

Chronic pancreatitis (CP) is a disease characterized by inflammatory recurrence that accompanies the development of pancreatic fibrosis. As the mystery of CP pathogenesis is gradually revealed, accumulating evidence suggests that the activation of pancreatic stellate cells (PSCs) and the appearance of a myofibroblast-like phenotype are the key gatekeepers in the development of CP. Targeting PSCs to prevent their activation and conversion to a myofibroblast-like phenotype, as well as increasing antioxidant capacity to counteract ongoing oxidative stress, are effective strategies for preventing or treating CP. Therefore, we reviewed the crosstalk between CP and pancreatic fibrosis, summarized the activation mechanisms of PSCs, and investigated potential CP therapeutic strategies targeting PSCs, including, but not limited to, anti-fibrosis therapy, antioxidant therapy, and gene therapy. Meanwhile, the above therapeutic strategies are selected in order to update the available phytopharmaceuticals as novel complementary or alternative approaches for the prevention and treatment of CP to clarify their potential mechanisms of action and their relevant molecular targets, aiming to provide the most comprehensive therapeutic treatment direction for CP and to bring new hope to CP patients.

Health Care Use among Medicare Beneficiaries with HIV and Depression during the COVID-19 Pandemic-United States, 2020.

Access and use of health care services are essential to health and well-being for people with HIV and HIV-related comorbidities. Health care use during the COVID-19 pandemic among Medicare beneficiaries (MBs) with concurrent HIV and depression has not been investigated. We used 2020 Medicare data to assess the percentage of MBs with claims for HIV and depression who also received hospitalization, outpatient diagnostic services, drug treatment, and outpatient procedures. We assessed person-level association between service receipt and HIV and depression, adjusting for known risk factors. MBs with claims for HIV and depression were more likely than those with neither claim to have claims for short-stay hospitalization, long-stay hospitalization, outpatient diagnostic services, prescription drugs, or outpatient procedures, supplies, and products. Non-White beneficiaries were more likely than White beneficiaries to be hospitalized but were less likely to receive drug treatment, outpatient diagnostic services, or outpatient procedures, supplies, and products during the pandemic. Significant disparities in health care use by race/ethnicity existed among MBs. Policymakers and practitioners can use these findings to implement public health policies and programs that reduce disparities in health care access and optimize use among vulnerable populations during a public health emergency.

Emergency department claims among Medicare beneficiaries with HIV, STDs, viral hepatitis or tuberculosis before and during the COVID-19 pandemic.

BACKGROUND: Changes in emergency department (ED) usage among US Medicare beneficiaries (MB) with fee-for-service claims for HIV, viral hepatitis, sexually transmitted diseases (STDs) or tuberculosis (TB) (HHST) services have not been assessed since the COVID-19 pandemic. METHODS: During 2006-20, we assessed the annual number of MB with each HHST per 1000 persons with ED claims for all conditions, and changes in demographic and geographic distribution of ED claimants for each HHST condition. RESULTS: Of all persons who attended an ED for any condition, 10.5 million (27.5%) were MB with ≥1 ED claim in 2006; that number (percentage) increased to 11.0 million (26.7%) in 2019 and decreased to 9.2 million (22.7%) in 2020; < 5 MB per 1000 ED population had HHST ED claims in 2020. The percentage increase in ED claims was higher for MB with STDs than for those with other HHST conditions, including a 10% decrease for MB with TB in 2020. CONCLUSIONS: Trends in ED usage for HHST conditions were associated with changes in demographic and geographic distribution among MB during 2006-20. Updated ED reimbursement policies and primary care practices among MB might improve prevention, diagnosis and treatment of HHST conditions in the future.

Electromyography-controlled gamified exercise system for the distal upper extremity: a usability assessment in subacute post-stroke patients.

PURPOSE: Movement repetition is known to play a key role in promoting functional improvements or maintaining functional levels in post-stroke hemiparetic patients. However, repetitive movements tend to be monotonous, making it challenging for patients to continue. Here, we developed a new gamified system to allow patients perform repetitive movements with enjoyment. The present study aimed to examine the usability of the system in subacute stroke patients. METHOD: The exercise system comprised an electromyography-controlled operating system that enabled users to play a virtual game by repetitive finger and wrist movements on the affected side. A total of 13 patients with upper-limb hemiparesis underwent a single bout of exercise using the system and assessed its usability, satisfactoriness, enjoyability, etc. using the System Usability Scale (SUS), Quebec User Evaluation of Satisfaction with assistive Technology (QUEST)-like questionnaire, and numerical rating scale (NRS). RESULTS: All the participants, who had a wide range of paretic levels, were able to perform the exercise using the system. Participants scored the system a median of 85.0 for SUS and 4.2 for the QUEST-like questionnaire, with an "excellent" in usability and "satisfied" in user satisfaction with the system. The median NRS scores for enjoyability, potential for continuous use, and effectiveness were 8.0, 9.0, and 9.0, respectively, which were greater than the scores for usual rehabilitation training for the upper extremity. CONCLUSIONS: The novel electromyography-controlled gamified exercise system may have sufficient usability and enjoyability to motivate patients with a wide range of paretic levels to perform repetitive finger and wrist movements.IMPLICATIONS FOR REHABILITATIONThe electromyography-controlled gamified exercise system had overall positive perspectives on the usability of the system.This exercise system could help motivate patients with a wide range of paretic levels to perform repetitive finger and wrist movements.

Bending and punching characteristics of aluminum sheets using the quasi-continuum method.

The nano-punching characteristics of single-crystalline aluminum are investigated using the quasi-continuum (QC) method. Four variables (i.e., crystal orientation, workpiece thickness, clearance between the punch and the substrate, and the taper angle of punch) are used to explore their effect during the nano-punching process. The shear stress distribution is used to express the punching effect on the punch and on both sides of the substrates. Besides, fracture strength, residual flash, and the atomic displacement vector are observed and discussed regarding the behaviors of the nano-punching process under various conditions. Based on the results, the Al workpiece with the X[111]Y[-110] orientation presents less lattice resistance during the punching process. Besides, the thickness of the workpiece has a significant effect on the punching quality. Workpieces with thickness values of 5 and 10 Å are more suitable for punching, due to stable loading and unloading stress-displacement curves and less residual flash on the cutting surfaces of these workpieces. In contrast, the effect of clearance has less impact on the punching behaviors of thinner workpieces. However, for thicker workpieces (i.e., 15 and 20 Å), a larger clearance will likely cause more residual flash. Furthermore, the taper angle of the punch should not be larger than 10°, otherwise, it might damage the workpiece and the substrate.

A Trade-Off for Maintenance of Multidrug-Resistant IncHI2 Plasmids in Salmonella enterica Serovar Typhimurium through Adaptive Evolution.

Understanding the fitness costs associated with plasmid carriage is a key to better understanding the mechanisms of plasmid maintenance in bacteria. In the current work, we performed multiple serial passages (63 days, 627.8 generations) to identify the compensatory mechanisms that Salmonella enterica serovar Typhimurium ATCC 14028 utilized to maintain the multidrug-resistant (MDR) IncHI2 plasmid pJXP9 in the presence and absence of antibiotic selection. The plasmid pJXP9 was maintained for hundreds of generations even without drug exposure. Endpoint evolved (the endpoint of evolution) S. Typhimurium bearing evolved plasmids displayed decreased growth lag times and a competitive advantage over ancestral pJXP9 plasmid-carrying ATCC 14028 strains. Genomic and transcriptomic analyses revealed that the fitness costs of carrying pJXP9 were derived from both specific plasmid genes and particularly the MDR regions and conjugation transfer region I and conflicts resulting from chromosome-plasmid gene interactions. Correspondingly, plasmid deletions of these regions could compensate for the fitness cost that was due to the plasmid carriage. The deletion extent and range of large fragments on the evolved plasmids, as well as the trajectory of deletion mutation, were related to the antibiotic treatment conditions. Furthermore, it is also adaptive evolution that chromosomal gene mutations and altered mRNA expression correlated with changed physiological functions of the bacterium, such as decreased flagellar motility, increased oxidative stress, and fumaric acid synthesis but increased Cu resistance in a given niche. Our findings indicated that plasmid maintenance evolves via a plasmid-bacterium adaptative evolutionary process that is a trade-off between vertical and horizontal transmission costs along with associated alterations in host bacterial physiology. IMPORTANCE The current idea that compensatory evolution processes can account for the "plasmid paradox" phenomenon associated with the maintenance of large costly plasmids in host bacteria has attracted much attention. Although many compensatory mutations have been discovered through various plasmid-host bacterial evolution experiments, the basis of the compensatory mechanisms and the nature of the bacteria themselves to address the fitness costs remain unclear. In addition, the genetic backgrounds of plasmids and strains involved in previous research were limited and clinical drug resistance such as the poorly understood compensatory evolution among clinically dominant multidrug-resistant plasmids or clones was rarely considered. The IncHI2 plasmid is widely distributed in Salmonella Typhimurium and plays an important role in the emergence and rapid spread of its multidrug resistance. In this study, the predominant multidrug-resistant IncHI2 plasmid pJXP9 and the standard Salmonella Typhimurium ATCC 14028 bacteria were used for evolution experiments under laboratory conditions. Our findings indicated that plasmid maintenance through experimental evolution of plasmid-host bacteria is a trade-off between increasing plasmid vertical transmission and impairing its horizontal transmission and bacterial physiological phenotypes, in which compensatory mutations and altered chromosomal expression profiles collectively contribute to alleviating plasmid-borne fitness cost. These results provided potential insights into understanding the relationship of coexistence between plasmids encoding antibiotic resistance and their bacterial hosts and provided a clue to the adaptive forces that shaped the evolution of these plasmids within bacteria and to predicting the evolution trajectory of antibiotic resistance.

Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression.

Preproenkephalin (PPE) is a precursor molecule for multiple endogenous opioid peptides Leu-enkephalin (ENK) and Met-ENK, which are involved in a wide variety of modulatory functions in the nervous system. Despite the functional importance of ENK in the brain, the effect of brain-derived factor(s) on PPE expression is unknown. We report the dual effect of neural epidermal growth factor (EGF)-likelike 2 (NELL2) on PPE gene expression. In cultured NIH3T3 cells, transfection of NELL2 expression vectors induced an inhibition of PPE transcription intracellularly, in parallel with downregulation of protein kinase C signaling pathways and extracellular signal-regulated kinase. Interestingly, these phenomena were reversed when synthetic NELL2 was administered extracellularly. The in vivo disruption of NELL2 synthesis resulted in an increase in PPE mRNA level in the rat brain, suggesting that the inhibitory action of intracellular NELL2 predominates the activation effect of extracellular NELL2 on PPE gene expression in the brain. Biochemical and molecular studies with mutant NELL2 structures further demonstrated the critical role of EGF-like repeat domains in NELL2 for regulation of PPE transcription. These are the first results to reveal the spatio-specific role of NELL2 in the homeostatic regulation of PPE gene expression.

Mitochondrial DNA methylation profiling of the human prefrontal cortex and nucleus accumbens: correlations with aging and drug use.

BACKGROUND: Despite the brain's high demand for energy, research on its epigenetics focuses on nuclear methylation, and much of the mitochondrial DNA methylation remains seldom investigated. With a focus on the nucleus accumbens (NAcc) and the prefrontal cortex (PFC), we aimed to identify the mitochondrial methylation signatures for (1) distinguishing the two brain areas, (2) correlating with aging, and (3) reflecting the influence of illicit drugs on the brain. RESULT: We collected the brain tissue in the NAcc and the PFC from the deceased individuals without (n = 39) and with (n = 14) drug use and used whole-genome bisulfite sequencing to cover cytosine sites in the mitochondrial genome. We first detected differential methylations between the NAcc and the PFC in the nonusers group (P = 3.89 × 10-9). These function-related methylation differences diminished in the drug use group due to the selective alteration in the NAcc. Then, we found the correlation between the methylation levels and the chronological ages in the nonusers group (R2 = 0.34 in the NAcc and 0.37 in the PFC). The epigenetic clocks in illicit drug users, especially in the ketamine users, were accelerated in both brain regions by comparison with the nonusers. Finally, we summarized the effect of the illicit drugs on the methylation, which could significantly differentiate the drug users from the nonusers (AUC = 0.88 in the NAcc, AUC = 0.94 in the PFC). CONCLUSION: The mitochondrial methylations were different between different brain areas, generally accumulated with aging, and sensitive to the effects of illicit drugs. We believed this is the first report to elucidate comprehensively the importance of mitochondrial DNA methylation in human brain.

Single-Step Fast Tissue Clearing of Thick Mouse Brain Tissue for Multi-Dimensional High-Resolution Imaging.

Recent advances in optical clearing techniques have dramatically improved deep tissue imaging by reducing the obscuring effects of light scattering and absorption. However, these optical clearing methods require specialized equipment or a lengthy undertaking with complex protocols that can lead to sample volume changes and distortion. In addition, the imaging of cleared tissues has limitations, such as fluorescence bleaching, harmful and foul-smelling solutions, and the difficulty of handling samples in high-viscosity refractive index (RI) matching solutions. To address the various limitations of thick tissue imaging, we developed an Aqueous high refractive Index matching and tissue Clearing solution for Imaging (termed AICI) with a one-step tissue clearing protocol that was easily made at a reasonable price in our own laboratory without any equipment. AICI can rapidly clear a 1 mm thick brain slice within 90 min with simultaneous RI matching, low viscosity, and a high refractive index (RI = 1.466), allowing the imaging of the sample without additional processing. We compared AICI with commercially available RI matching solutions, including optical clear agents (OCAs), for tissue clearing. The viscosity of AICI is closer to that of water compared with other RI matching solutions, and there was a less than 2.3% expansion in the tissue linear morphology during 24 h exposure to AICI. Moreover, AICI remained fluid over 30 days of air exposure, and the EGFP fluorescence signal was only reduced to ~65% after 10 days. AICI showed a limited clearing of brain tissue >3 mm thick. However, fine neuronal structures, such as dendritic spines and axonal boutons, could still be imaged in thick brain slices treated with AICI. Therefore, AICI is useful not only for the three-dimensional (3D) high-resolution identification of neuronal structures, but also for the examination of multiple structural imaging by neuronal distribution, projection, and gene expression in deep brain tissue. AICI is applicable beyond the imaging of fluorescent antibodies and dyes, and can clear a variety of tissue types, making it broadly useful to researchers for optical imaging applications.

Deep Learning-Based Grimace Scoring Is Comparable to Human Scoring in a Mouse Migraine Model.

Pain assessment is essential for preclinical and clinical studies on pain. The mouse grimace scale (MGS), consisting of five grimace action units, is a reliable measurement of spontaneous pain in mice. However, MGS scoring is labor-intensive and time-consuming. Deep learning can be applied for the automatic assessment of spontaneous pain. We developed a deep learning model, the DeepMGS, that automatically crops mouse face images, predicts action unit scores and total scores on the MGS, and finally infers whether pain exists. We then compared the performance of DeepMGS with that of experienced and apprentice human scorers. The DeepMGS achieved an accuracy of 70-90% in identifying the five action units of the MGS, and its performance (correlation coefficient = 0.83) highly correlated with that of an experienced human scorer in total MGS scores. In classifying pain and no pain conditions, the DeepMGS is comparable to the experienced human scorer and superior to the apprentice human scorers. Heatmaps generated by gradient-weighted class activation mapping indicate that the DeepMGS accurately focuses on MGS-relevant areas in mouse face images. These findings support that the DeepMGS can be applied for quantifying spontaneous pain in mice, implying its potential application for predicting other painful conditions from facial images.

Plasmid and chromosomal copies of blaCMY-2 mediate resistance to third-generation cephalosporins in Escherichia coli from food animals in China.

The use of antimicrobials in food animals is the major determinant for the propagation of resistant bacteria in the animal reservoir. The objective of this study was to investigate the presence and distribution of third-generation cephalosporin (3GC) -resistant and plasmid-mediated AmpC (pAmpC)-producing Escherichia coli isolated from food animals in Southern China. In total, 744 3GC-resistant and 40 blaCMY-2-positive E. coli strains were recovered from 1656 food animal fecal samples across five rearing regions. The blaCMY-2 genes were located on IncC, IncFIB or IncI1 type plasmids in 12 E. coli isolates. In the other 22 isolates, S1-PFGE and hybridization analyses revealed that the blaCMY-2 gene was chromosomally located and demonstrated a high prevalence of the chromosomally encoded blaCMY-2 gene in E. coli. Plasmid stability and growth curve experiments demonstrated that IncI1, IncC and IncFIB plasmids can exist stably in the host bacteria and with a low growth burden and may be the reason these plasmids can be widely disseminated in breeding environments. Whole genome sequencing indicated that ISEcp1 and IS1294 played important roles in blaCMY-2 transfer to both plasmids and the chromosome. Our study confirmed that blaCMY-2 mediated resistance of food animal-derived E. coli to 3GC and highlights the urgent need for appropriate monitoring programmes.

Association of Urban-Rural Residence and Concurrent HIV Infection and Opioid Use Disorder Among Medicare Beneficiaries-United States, 2020.

Published research provides minimal insights into variation by urban or rural residence of HIV infection risk and injection drug use. We used the 2020 Medicare claims data to assess the association of urban-rural residence and concurrent HIV infection and opioid use disorder (OUD), adjusted for demographic risk factors, among Medicare beneficiaries (MBs) with fee-for-service claims paid during 2020. Medicare beneficiaries with both HIV infection and OUD were more likely than those without to be aged ≤64 years, male, Black, residing in the U.S. Northeast, residing in an urban county, and to have one or more comorbid condition. Medicare beneficiaries who lived in urban counties had higher odds (adjusted odds ratio 4.04; 95% confidence interval 3.72, 4.39) of having HIV and OUD than those who lived in rural counties. Urban-rural residence was associated with concurrent HIV infection and OUD, independent of age, sex, race/ethnicity, and comorbidity among MBs with claims paid during 2020.

Formation, Transmission, and Dynamic Evolution of a Multidrug-Resistant Chromosomally Integrated Plasmid in Salmonella Spp.

IncHI2 plasmids, possessing high flexibility and genetic plasticity, play a vital role in the acquisition and transmission of resistance determinants. Polymorphic mobile genetic elements (MGEs) generated by a chromosomally integrated IncHI2 plasmid in an individual Salmonella isolate have not yet been detected, and the mechanisms of the formation, excision, and dynamic evolution of a multidrug-resistant chromosomally integrated plasmid (MRCP) have remained obscure. Herein, we identified a 260-kb bla CTX-M-55-qnrS1-bearing IncHI2 plasmid within a Salmonella Muenster strain. Plenty of heterogeneous MGEs (new Escherichia coli chromosomally integrated plasmid or circular plasmids with different profiles) were yielded when this MRCP was conjugated into E. coli J53 with a transfer frequency of 10-4-10-5 transconjugants per donor. A bioinformatic analysis indicated that replicative transposition and homologous recombination of IS26 elements were particularly active, and the truncated Tn1721 also played a vital role in the formation of MRCP offspring. More importantly, when released from the chromosome, MRCP could capture and co-transfer adjacent chromosomal segments to form larger plasmid progeny than itself. Stability and growth kinetics assays showed that the biological characteristics of MRCP progeny were differentiated. This study provides an insight into a flexible existence of MRCP. The conversion between vertical and horizontal transmission endowed MRCP with genetic stability as a chromosomal coding structure and transferability as extra-chromosomal elements. This alternation may accelerate the acquisition and persistence of antibiotic resistance of clinical pathogens and enhance their ability to respond to adverse environments, which poses a great challenge to the traditional antibiotic treatment.

Provisional COVID-19 Age-Adjusted Death Rates, by Race and Ethnicity - United States, 2020-2021.

Disparities in COVID-19 death rates by race and ethnicity have been reported in the United States (1,2). In response to these disparities, preventive, medical care, and social service assistance programs were implemented to lessen disparities in COVID-19 outcomes, including grants to support state, tribal, local, and territorial health department responses (3). The potential impact of such efforts on annual changes in racial and ethnic disparities in mortality rates that identify COVID-19 as the underlying cause of death has not been previously reported. This analysis used U.S. provisional mortality data from death certificates collected by CDC's National Vital Statistics System (NVSS) to estimate changes in COVID-19-related age-adjusted death rates (AADRs) by race and ethnicity during 2020-2021. Compared with non-Hispanic multiracial persons (the group with the lowest death rate), significant decreases in AADR ratios occurred during 2020-2021 among non-Hispanic American Indian or Alaska Native (AI/AN) persons (34.0%), non-Hispanic Asian (Asian) persons (37.6%), non-Hispanic Black or African American (Black) persons (40.2%), Hispanic persons (37.1%), and non-Hispanic White (White) persons (14%); a non-statistically significant 7.2% increase in AADR ratio occurred among non-Hispanic Native Hawaiian or other Pacific Islander (NH/OPI) persons. Despite reductions in AADR disparities from 2020 to 2021, large disparities in AADR by race and ethnicity remained in 2021. Providing effective preventive interventions, including vaccination and clinical care, to all communities in proportion to their need for these interventions is necessary to reduce racial and ethnic disparities in COVID-19 deaths.