Unmet Needs for Ancillary Services by Provider Type Among People With Diagnosed Human Immunodeficiency Virus.

Background: Unmet needs for ancillary services are substantial among people with human immunodeficiency virus (PWH), and provider type could influence the prevalence of unmet needs for these services. Methods: Data from a national probability sample of PWH were analyzed from the Centers for Disease Control and Prevention's Medical Monitoring Project. We analyzed 2019 data on people who had ≥1 encounter with a human immunodeficiency virus (HIV) care provider (N = 3413) and their care facilities. We assessed the proportion of needs that were unmet for individual ancillary services, overall and by HIV care provider type, including infectious disease (ID) physicians, non-ID physicians, nurse practitioners, and physician assistants. We calculated prevalence differences (PDs) with predicted marginal means to assess differences between groups. Results: An estimated 98.2% of patients reported ≥1 need for an ancillary service, and of those 46% had ≥1 unmet need. Compared with patients of ID physicians, needs for many ancillary services were higher among patients of other provider types. However, even after adjustment, patients of non-ID physicians had lower unmet needs for dental care (adjusted PD, -5.6 [95% confidence interval {CI}, -9.9 to -1.3]), and patients of nurse practitioners had lower unmet needs for HIV case management services (adjusted PD, -5.4 [95% CI, -9.4 to -1.4]), compared with patients of ID physicians. Conclusions: Although needs were greater among patients of providers other than ID physicians, many of these needs may be met by existing support systems at HIV care facilities. However, additional resources may be needed to address unmet needs for dental care and HIV case management among patients of ID physicians.

Unraveling host-pathogen dynamics in a murine Model of septic peritonitis induced by vancomycin-resistant Enterococcus faecium.

Vancomycin-resistant Enterococcus faecium (E. faecium) infection is associated with higher mortality rates. Previous studies have emphasized the importance of innate immune cells and signalling pathways in clearing E. faecium, but a comprehensive analysis of host-pathogen interactions is lacking. Here, we investigated the interplay of host and E. faecium in a murine model of septic peritonitis. Following injection with a sublethal dose, we observed significantly increased murine sepsis score and histological score, decreased weight and bacterial burden, neutrophils and macrophages infiltration, and comprehensive activation of cytokine-mediated signalling pathway. In mice receiving a lethal dose, hypothermia significantly improved survival, reduced bacterial burden, cytokines, and CD86 expression of MHC-II+ recruited macrophages compared to the normothermia group. A mathematical model constructed by observational data from 80 animals, recapitulated the host-pathogen interplay, and further verified the benefits of hypothermia. These findings indicate that E. faecium triggers a severe activation of cytokine-mediated signalling pathway, and hypothermia can improve outcomes by reducing bacterial burden and inflammation.

HEARTSVG: a fast and accurate method for identifying spatially variable genes in large-scale spatial transcriptomics.

Identifying spatially variable genes (SVGs) is crucial for understanding the spatiotemporal characteristics of diseases and tissue structures, posing a distinctive challenge in spatial transcriptomics research. We propose HEARTSVG, a distribution-free, test-based method for fast and accurately identifying spatially variable genes in large-scale spatial transcriptomic data. Extensive simulations demonstrate that HEARTSVG outperforms state-of-the-art methods with higher F 1 scores (average F 1 Score=0.948), improved computational efficiency, scalability, and reduced false positives (FPs). Through analysis of twelve real datasets from various spatial transcriptomic technologies, HEARTSVG identifies a greater number of biologically significant SVGs (average AUC = 0.792) than other comparative methods without prespecifying spatial patterns. Furthermore, by clustering SVGs, we uncover two distinct tumor spatial domains characterized by unique spatial expression patterns, spatial-temporal locations, and biological functions in human colorectal cancer data, unraveling the complexity of tumors.

Learning locality-sensitive bucketing functions.

MOTIVATION: Many tasks in sequence analysis ask to identify biologically related sequences in a large set. The edit distance, being a sensible model for both evolution and sequencing error, is widely used in these tasks as a measure. The resulting computational problem-to recognize all pairs of sequences within a small edit distance-turns out to be exceedingly difficult, since the edit distance is known to be notoriously expensive to compute and that all-versus-all comparison is simply not acceptable with millions or billions of sequences. Among many attempts, we recently proposed the locality-sensitive bucketing (LSB) functions to meet this challenge. Formally, a (d1,d2)-LSB function sends sequences into multiple buckets with the guarantee that pairs of sequences of edit distance at most d1 can be found within a same bucket while those of edit distance at least d2 do not share any. LSB functions generalize the locality-sensitive hashing (LSH) functions and admit favorable properties, with a notable highlight being that optimal LSB functions for certain (d1,d2) exist. LSB functions hold the potential of solving above problems optimally, but the existence of LSB functions for more general (d1,d2) remains unclear, let alone constructing them for practical use. RESULTS: In this work, we aim to utilize machine learning techniques to train LSB functions. With the development of a novel loss function and insights in the neural network structures that can potentially extend beyond this specific task, we obtained LSB functions that exhibit nearly perfect accuracy for certain (d1,d2), matching our theoretical results, and high accuracy for many others. Comparing to the state-of-the-art LSH method Order Min Hash, the trained LSB functions achieve a 2- to 5-fold improvement on the sensitivity of recognizing similar sequences. An experiment on analyzing erroneous cell barcode data is also included to demonstrate the application of the trained LSB functions. AVAILABILITY AND IMPLEMENTATION: The code for the training process and the structure of trained models are freely available at https://github.com/Shao-Group/lsb-learn.

Antimicrobial and Antibiofilm Effects of Bithionol against Mycobacterium abscessus.

Mycobacterium abscessus (M. abscessus) is a multidrug-resistant nontuberculous mycobacterium (NTM) that is responsible for a wide spectrum of infections in humans. The lack of effective bactericidal drugs and the formation of biofilm make its clinical treatment very difficult. The FDA-approved drug library containing 3048 marketed and pharmacopeial drugs or compounds was screened at 20 µM against M. abscessus type strain 19977 in 7H9 medium, and 62 hits with potential antimicrobial activity against M. abscessus were identified. Among them, bithionol, a clinically approved antiparasitic agent, showed excellent antibacterial activity and inhibited the growth of three different subtypes of M. abscessus from 0.625 µM to 2.5 µM. We confirmed the bactericidal activity of bithionol by the MBC/MIC ratio being ≤4 and the time-kill curve study and also electron microscopy study. Interestingly, it was found that at 128 µg/mL, bithionol could completely eliminate biofilms after 48h, demonstrating an outstanding antibiofilm capability compared to commonly used antibiotics. Additionally, bithionol could eliminate 99.9% of biofilm bacteria at 64 µg/mL, 99% at 32 µg/mL, and 90% at 16 µg/mL. Therefore, bithionol may be a potential candidate for the treatment of M. abscessus infections due to its significant antimicrobial and antibiofilm activities.

Trifolium repens L. recruits root-associated Microbacterium species to adapt to heavy metal stress in an abandoned Pb-Zn mining area.

Root-associated microbiota provide great fitness to hosts under environmental stress. However, the underlying microecological mechanisms controlling the interaction between heavy metal-stressed plants and the microbiota are poorly understood. In this study, we screened and isolated representative amplicon sequence variants (strain M4) from rhizosphere soil samples of Trifolium repens L. growing in areas with high concentrations of heavy metals. To investigate the microecological mechanisms by which T. repens adapts to heavy metal stress in abandoned mining areas, we conducted potting experiments, bacterial growth promotion experiments, biofilm formation experiments, and chemotaxis experiments. The results showed that high concentrations of heavy metals significantly altered the rhizosphere bacterial community structure of T. repens and significantly enriched Microbacterium sp. Strain M4 was demonstrated to significantly increased the biomass and root length of T. repens under heavy metal stress. Additionally, L-proline and stigmasterol could promote bacterial growth and biofilm formation and induce chemotaxis for strain M4, suggesting that they are key rhizosphere secretions of T. repens for Microbacterium sp. recruitment. Our results suggested that T. repens adapted the heavy metal stress by reshaping rhizosphere secretions to modify the rhizosphere microbiota.

Non-invasive assessment of proarrhythmic risks associated with isoprenaline and the dietary supplement ingredient synephrine using human induced pluripotent stem cell-derived cardiomyocytes.

Background: There have been conflicting reports about the proarrhythmic risk of p-synephrine (SYN). To address this, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with the microelectrode array (MEA) system have been utilized to assess arrhythmia risks, particularly in the context of adrenomimetic drugs. Aim: This study aims to determine whether MEA recordings from hiPSC-CMs could predict the proarrhythmic risk of adrenomimetic drugs and to investigate the cardiovascular effects and mechanisms of SYN. Materials and methods: We employed MEA recordings to assess the electrophysiological properties of hiPSC-CMs and conducted concentration-response analyses to evaluate the effects of SYN and Isoprenaline (ISO) on beating rate and contractility. A risk scoring system for proarrhythmic risks was established based on hiPSC-CMs in this study. ISO, a classic beta-adrenergic drug, was also evaluated. Furthermore, the study evaluated the risk of SYN and recorded the concentration-response of beating rate, contractility and the change in the presence or absence of selective ß1, ß2 and ß3 adrenergic blockers. Results: Our results suggested that ISO carries a high risk of inducing arrhythmias, aligning with existing literature. SYN caused a 30% prolongation of the field potential duration (FPD) at a concentration of 206.326 µM, a change significantly different from baseline measurements and control treatments. The half maximal effective concentration (EC50) of SYN (3.31 µM) to affect hiPSC-CM beating rate is much higher than that of ISO (18.00 nM). The effect of SYN at an EC50 of 3.31 µM is about ten times more potent in hiPSC-CMs compared to neonatal rat cardiomyocytes (34.12 µM). SYN increased the contractility of cardiomyocytes by 29.97 ± 11.65%, compared to ISO's increase of 50.56 ± 24.15%. ß1 receptor blockers almost eliminated the beating rate increase induced by both ISO and SYN, while neither ß2 nor ß3 blockers had a complete inhibitory effect. Conclusion: The MEA and hiPSC-CM system could effectively predict the risk of adrenomimetic drugs. The study concludes that the proarrhythmia risk of SYN at conventional doses is low. SYN is more sensitive in increasing beating rate and contractility in human cardiomyocytes compared to rats, primarily activating ß1 receptor.

Identification of ARF Genes and Elucidation of the Regulatory Effects of PsARF16a on the Dormancy of Tree Peony Plantlets.

The low survival rate of transplanted plantlets, which has limited the utility of tissue-culture-based methods for the rapid propagation of tree peonies, is due to plantlet dormancy after rooting. We previously determined that the auxin response factor PsARF may be a key regulator of tree peony dormancy. To clarify the mechanism mediating tree peony plantlet dormancy, PsARF genes were systematically identified and analyzed. Additionally, PsARF16a was transiently expressed in the leaves of tree peony plantlets to examine its regulatory effects on a downstream gene network. Nineteen PsARF genes were identified and divided into four classes. All PsARF genes encoded proteins with conserved B3 and ARF domains. The number of motifs, exons, and introns varied between PsARF genes in different classes. The overexpression of PsARF16a altered the expression of NCED, ZEP, PYL, GA2ox1, GID1, and other key genes in abscisic acid (ABA) and gibberellin (GA) signal transduction pathways, thereby promoting ABA synthesis and decreasing GA synthesis. Significant changes to the expression of some key genes contributing to starch and sugar metabolism (e.g., AMY2A, BAM3, BGLU, STP, and SUS2) may be associated with the gradual conversion of sugar into starch. This study provides important insights into PsARF functions in tree peonies.

Molecular transmission network analysis of newly diagnosed HIV-1 infections in Nanjing from 2019 to 2021.

OBJECTIVE: The objective of this study was to conduct a comprehensive analysis of the molecular transmission networks and transmitted drug resistance (TDR) patterns among individuals newly diagnosed with HIV-1 in Nanjing. METHODS: Plasma samples were collected from newly diagnosed HIV patients in Nanjing between 2019 and 2021. The HIV pol gene was amplified, and the resulting sequences were utilized for determining TDR, identifying viral subtypes, and constructing molecular transmission network. Logistic regression analyses were employed to investigate the epidemiological characteristics associated with molecular transmission clusters. RESULTS: A total of 1161 HIV pol sequences were successfully extracted from newly diagnosed individuals, each accompanied by reliable epidemiologic information. The analysis revealed the presence of multiple HIV-1 subtypes, with CRF 07_BC (40.57%) and CRF01_AE (38.42%) being the most prevalent. Additionally, six other subtypes and unique recombinant forms (URFs) were identified. The prevalence of TDR among the newly diagnosed cases was 7.84% during the study period. Employing a genetic distance threshold of 1.50%, the construction of the molecular transmission network resulted in the identification of 137 clusters, encompassing 613 nodes, which accounted for approximately 52.80% of the cases. Multivariate analysis indicated that individuals within these clusters were more likely to be aged ≥ 60, unemployed, baseline CD4 cell count ≥ 200 cells/mm3, and infected with the CRF119_0107 (P < 0.05). Furthermore, the analysis of larger clusters revealed that individuals aged ≥ 60, peasants, those without TDR, and individuals infected with the CRF119_0107 were more likely to be part of these clusters. CONCLUSIONS: This study revealed the high risk of local HIV transmission and high TDR prevalence in Nanjing, especially the rapid spread of CRF119_0107. It is crucial to implement targeted interventions for the molecular transmission clusters identified in this study to effectively control the HIV epidemic.

Megastigmane glycosides from the traditional Uighur medicine Cydonia oblonga Mill.

Phytochemical investigation on the fruits of Cydonia oblonga Mill., a traditional Uighur medicine, led to the isolation of seven undescribed and nine known megastigmane glycosides. Their structures including absolute configurations were characterized by an extensive analysis of spectroscopic data including HRESIMS and NMR, combined with ECD calculations. Additionally, compounds 1, 2, 4, and 6-16 exhibited anti-inflammatory activity by inhibiting the secretion of cytokines TNF-α and IL-6 in RAW264.7 cells induced by lipopolysaccharides (LPS) with inhibitory rates of 10.79%-44.58% at 20 µM.

Coronary computed tomographic angiography-derived anatomic and hemodynamic plaque characteristics in prediction of cardiovascular events.

This study investigated the association of anatomic and hemodynamic plaque characteristics based on deep learning coronary computed tomography angiography (CCTA) with high-risk plaques that caused subsequent major adverse cardiovascular events (MACE). A retrospective analysis was conducted on patients who underwent CCTA between 1 month and 3 years prior to the occurrence of a MACE. Deep learning and computational fluid dynamics algorithms based on CCTA were applied to extract adverse plaque characteristics (low-attenuation plaque, positive remodeling, napkin-ring sign, and spotty calcification), and hemodynamic parameters (fractional flow reserve derived by coronary computed tomographic angiography [FFRCT], change in FFRCT across the lesion [△FFRCT], wall shear stress [WSS], and axial plaque stress [APS]). Correlation analysis, logistic regression, and Cox proportional risk analysis were conducted to understand the relationship between these measures and the occurrence of MACE and assess the value of hemodynamic parameters in predicting the incidence of MACE events and their prognosis. Our study included 86 patients with a total of 134 vessels exhibiting plaque formation and 83 culprit vessels with a subsequent coronary event. Culprit vessels had percent diameter stenosis [%DS] (0.54 ± 0.16 vs. 0.62 ± 0.13, P = 0.003), larger non-calcified plaque volume (45.8 vs. 101.7, P < 0.001), larger low-attenuation plaque volume (3.6 vs. 14.5, P < 0.001), more lesions with ≥ 3 adverse plaque characteristics (APC) (4 vs.26, P = 0.002), and worse hemodynamic features of adverse plaque. FFRCT demonstrated better visualization of maximum achievable flow in the presence of coronary stenosis and better correlation with the stenosis severity, while maximum of wall shear stress (WSSmax) was highly correlated with low-attenuation plaques and APC. The inclusion of hemodynamic parameters improved the efficacy of the predictive model, and a high WSS suggested a higher probability of MACE. Hemodynamic parameters based on CCTA are significantly correlated with plaque morphology. Importantly, integrating CCTA-derived parameters can refine the predictive performance of MACE occurrence.

Roles of vaporization and thermal decomposition in the dynamic evolution of laser-induced bubble on the surface of a submerged metal plate.

This paper aims to explain when the vaporization or thermal decomposition prevails during laser-induced bubble growth and how they influence bubble morphology. Bubbles were generated by irradiating a 304 stainless steel plate submerged in degassed water using millisecond lasers with a pulse width of 0.4 ms and powers of 1.6 kW and 3.2 kW, respectively. The dynamic evolution of bubbles was recorded by a high-speed camera. Moreover, the numerical models were developed to obtain a vaporization model and a decomposition model by incorporating the source terms due to the vaporization and decomposition mass fluxes into the governing equations, respectively. The simulated dynamic bubble evolution is consistent with the experimental results. When the laser power is 1.6 kW, a thin-layer bubble is formed, which gradually shrinks and eventually disappears after the laser stops irradiating. When the laser power is 3.2 kW, a spherical bubble is formed, and its volume decreases significantly after the laser stops irradiating. Subsequently, it remains relatively stable during the observation period. The fundamental reason for the difference between the bubble morphologies obtained from the vaporization model and the decomposition model lies in the presence of a condensation zone in the gas phase. When water vaporization or thermal decomposition dominates, the temperatures obtained from the models align with the decomposition ratios at varying temperatures reported in the literature. Our findings are significant for understanding the dynamic behavior of bubbles, with implications for various laser processing underwater.

Antimicrobial drugs for Parkinson's disease: Existing therapeutic strategies and novel drugs exploration.

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by loss of dopaminergic neurons in the substantia nigra, as well as the abnormal accumulation of misfolded α-synuclein. Clinically, PD is featured by typical motor symptoms and some non-motor symptoms. Up to now, although considerable progress has been made in understanding the pathogenesis of PD, there is still no effective therapeutic treatment for the disease. Thus, exploring new therapeutic strategies has been a topic that needs to be addressed urgently. Noteworthy, with the proposal of the microbiota-gut-brain axis theory, antimicrobial drugs have received significant attention due to their effects on regulating the intestinal microbiota. Nowadays, there is growing evidence showing that some antimicrobial drugs may be promising drugs for the treatment of PD. Data from pre-clinical and clinical studies have shown that some antimicrobial drugs may play neuroprotective roles in PD by modulating multiple biochemical and molecular pathways, including reducing α-synuclein aggregation, inhibiting neuroinflammation, regulating mitochondrial structure and function, as well as suppressing oxidative stress. In this paper, we summarized the effects of some antimicrobial drugs on PD treatment from recent pre-clinical and clinical studies. Then, we further discussed the potential of a few antimicrobial drugs for treating PD based on molecular docking and molecular dynamics simulation. Importantly, we highlighted the potential of clorobiocin as the therapeutic strategy for PD owing to its ability to inhibit α-synuclein aggregation. These results will help us to better understand the potential of antimicrobial drugs in treating PD and how antimicrobial drugs may alleviate or reverse the pathological symptoms of PD.

Progress towards achieving national goals for improved quality of life among cis-gender Black women with HIV.

Data from the CDC's Medical Monitoring Project indicate that the United States is on track to meet one of five National HIV/AIDS Strategy (NHAS) Quality of Life goals among cisgender Black women, specifically, hunger/food insecurity. Substantial work needs to be done to improve self-rated health and to decrease unmet need for mental health services. Enhanced and coordinated action are necessary to reach all Quality of Life goals in this NHAS priority population.

The Closer Vicinity to Treated Vertebrae in Percutaneous Vertebroplasty, the Higher Rate of New Vertebral Compression Fractures at Follow-up.

OBJECTIVE: To investigate whether risk of new vertebral compression fractures (NVCFs) was associated with vicinity to treated vertebrae in percutaneous vertebroplasty (PVP) for osteoporotic vertebral compression fractures (OVCFs). METHODS: All OVCF (T6-L5) patients treated with PVP between January 2016 and December 2020 were retrospectively reviewed. Vicinity to treated vertebrae was defined as the number of vertebrae between an untreated and its closest treated level. The closest treated level was chosen as reference vertebra. Clinical, radiologic, and surgical parameters were compared between groups of reference vertebrae for each vicinity NVCF. RESULTS: In total, 1348 patients with 1592 fractured and 14,584 normal vertebrae were enrolled. NVCF was identified in 20.1% (271 of 1348) patients in 2.2% (319 of 14584) vertebrae in a mean follow-up time of 24.3 ± 11.9 months. Rate of NVCF in vicinity 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 level were 4.6% (130 of 2808), 2.4% (62 of 2558), 1.8% (42 of 2365), 1.5% (31 of 2131), 1.3% (23 of 1739), 1.3% (17 of 1298), 0.8% (7 of 847), 0.9% (4 of 450), 0.8% (2 of 245), 0.9% (1 of 117), and 0% (0 of 26), respectively. Rate of NVCF in vicinity 1 level was significantly higher than that in vicinity 2, 3, 4, 5, 6, 7, 8, and 9 level, respectively. However, compared to reference vertebrae for vicinity 1 NVCF, any clinical, radiologic, or surgical parameters were not significantly different in those for vicinity 2, 3, and 4 NVCF, respectively. CONCLUSIONS: The closer vicinity to treated vertebrae in PVP, the higher rate of NVCF at follow-up. However, any clinical, radiologic, or surgical parameters might not matter in this phenomenon of vicinity-related NVCF.

The roles of B cells in cardiovascular diseases.

Damage to the heart can start the repair process and cause cardiac remodeling. B cells play an important role in this process. B cells are recruited to the injured place and activate cardiac remodeling through secreting antibodies and cytokines. Different types of B cells showed specific functions in the heart. Among all types of B cells, heart-associated B cells play a vital role in the heart by secreting TGFß1. B cells participate in the activation of fibroblasts and promote cardiac fibrosis. Four subtypes of B cells in the heart revealed the relationship between the B cells' heterogeneity and cardiac remodeling. Many cardiovascular diseases like atherosclerosis, heart failure (HF), hypertension, myocardial infarction (MI), and dilated cardiomyopathy (DCM) are related to B cells. The primary mechanisms of these B cell-related activities will be discussed in this review, which may also suggest potential novel therapeutic targets.

Learning autonomous race driving with action mapping reinforcement learning.

Autonomous race driving poses a complex control challenge as vehicles must be operated at the edge of their handling limits to reduce lap times while respecting physical and safety constraints. This paper presents a novel reinforcement learning (RL)-based approach, incorporating the action mapping (AM) mechanism to manage state-dependent input constraints arising from limited tire-road friction. A numerical approximation method is proposed to implement AM, addressing the complex dynamics associated with the friction constraints. The AM mechanism also allows the learned driving policy to be generalized to different friction conditions. Experimental results in our developed race simulator demonstrate that the proposed AM-RL approach achieves superior lap times and better success rates compared to the conventional RL-based approaches. The generalization capability of driving policy with AM is also validated in the experiments.

AN698/40746067 suppresses bone marrow adiposity to ameliorate hyperlipidemia-induced osteoporosis through targeted inhibition of ENTR1.

Hyperlipidemia-induced osteoporosis is marked by increased bone marrow adiposity, and treatment with statins for hyperlipidemia often leads to new-onset osteoporosis. Endosome-associated trafficking regulator 1 (ENTR1) has been found to interact with different proteins in pathophysiology, but its exact role in adipogenesis is not yet understood. This research aimed to explore the role of ENTR1 in adipogenesis and to discover a new small molecule that targets ENTR1 for evaluating its effectiveness in treating hyperlipidemia-induced osteoporosis. We found that ENTR1 expression increased during the adipogenesis of bone marrow mesenchymal cells (BMSCs). ENTR1 gain- and loss-of-function assays significantly enhanced lipid droplets formation. Mechanistically, ENTR1 binds peroxisome proliferator-activated receptor γ (PPARγ) and enhances its expression, thereby elevating adipogenic markers including C/EBPα and LDLR. Therapeutically, AN698/40746067 attenuated adipogenesis by targeting ENTR1 to suppress PPARγ. In vivo, AN698/40746067 reduced bone marrow adiposity and bone loss, as well as prevented lipogenesis-related obesity, inflammation, steatohepatitis, and abnormal serum lipid levels during hyperlipidemia. Together, these findings suggest that ENTR1 facilitates adipogenesis by PPARγ involved in BMSCs' differentiation, and targeted inhibition of ENTR1 by AN698/40746067 may offer a promising therapy for addressing lipogenesis-related challenges and alleviating osteoporosis following hyperlipidemia.