Severity Identification of Graves Orbitopathy via Random Forest Algorithm.

This study aims to establish a random forest model for detecting the severity of Graves Orbitopathy (GO) and identify significant classification factors. This is a hospital-based study of 199 patients with GO that were collected between December 2019 and February 2022. Clinical information was collected from medical records. The severity of GO can be categorized as mild, moderate-to-severe, and sight-threatening GO based on guidelines of the European Group on Graves' orbitopathy. A random forest model was constructed according to the risk factors of GO and the main ocular symptoms of patients to differentiate mild GO from severe GO and finally was compared with logistic regression analysis, Support Vector Machine (SVM), and Naive Bayes. A random forest model with 15 variables was constructed. Blurred vision, disease course, thyroid-stimulating hormone receptor antibodies, and age ranked high both in mini-decreased gini and mini decrease accuracy. The accuracy, positive predictive value, negative predictive value, and the F1 Score of the random forest model are 0.83, 0.82, 0.86, and 0.82, respectively. Compared to the three other models, our random forest model showed a more reliable performance based on AUC (0.85 vs. 0.83 vs. 0.80 vs. 0.76) and accuracy (0.83 vs. 0.78 vs. 0.77 vs. 0.70). In conclusion, this study shows the potential for applying a random forest model as a complementary tool to differentiate GO severity.

Low toxicity contributes to Sporothrix globosa invade the skin of patients in low-epidemic areas of China.

OBJECTIVE: This study aims to assess the clinical characteristics of sporotrichosis in low-endemic areas of China, including the prevalence geography, genotypic traits of patients, clinical manifestations, and strain virulence and drug sensitivities. The objective is to improve the currently used clinical management strategies for sporotrichosis. METHODS: Retrospective data were collected from patients diagnosed with sporotrichosis through fungal culture identification. The isolates from purified cultures underwent identification using CAL (Calmodulin) gene sequencing. Virulence of each strain was assessed using a Galleria mellonella (G. mellonella) larvae infection model. In vitro susceptibility testing against commonly used clinical antifungal agents for sporotrichosis was conducted following CLSI criteria. RESULTS: In our low-endemic region for sporotrichosis, the majority of cases (23) were observed in middle-aged and elderly women with a history of trauma, with a higher incidence during winter and spring. All clinical isolates were identified as Sporothrix globosa (S. globosa). The G. mellonella larvae infection model indicated independent and dose-dependent virulence among strains, with varying toxicity levels demonstrated by the degree of melanization of the G. mellonella. Surprisingly, lymphocutaneous types caused by S. globosa exhibited lower in vitro virulence but were more common in affected skin. In addition, all S.globosa strains displayed high resistances to fluconazole, while remaining highly susceptible to terbinafine, itraconazole and amphotericin B. CONCLUSION: Given the predominance of elderly women engaged in agricultural labour in our region, which is a low-epidemic areas, they should be considered as crucial targets for sporotrichosis monitoring. S. globosa appears to be the sole causative agent locally. However, varying degrees of melanization in larvae were observed among these isolates, indicating a divergence in their virulence. Itraconazole, terbinafine and amphotericin B remain viable first-line antifungal options for treating S.globosa infection.

An original aneuploidy-related gene model for predicting lung adenocarcinoma survival and guiding therapy.

Aneuploidy is a hallmark of cancers, but the role of aneuploidy-related genes in lung adenocarcinoma (LUAD) and their prognostic value remain elusive. Gene expression and copy number variation (CNV) data were enrolled from TCGA and GEO database. Consistency clustering analysis was performed for molecular cluster. Tumor microenvironment was assessed by the xCell and ESTIMATE algorithm. Limma package was used for selecting differentially expressed genes (DEGs). LASSO and stepwise multivariate Cox regression analysis were used to establish an aneuploidy-related riskscore (ARS) signature. GDSC database was conducted to predict drug sensitivity. A nomogram was designed by rms R package. TCGA-LUAD patients were stratified into 3 clusters based on CNV data. The C1 cluster displayed the optimal survival advantage and highest inflammatory infiltration. Based on integrated intersecting DEGs, we constructed a 6-gene ARS model, which showed effective prediction for patient's survival. Drug sensitivity test predicted possible sensitive drugs in two risk groups. Additionally, the nomogram exhibited great predictive clinical treatment benefits. We established a 6-gene aneuploidy-related signature that could effectively predict the survival and therapy for LUAD patients. Additionally, the ARS model and nomogram could offer guidance for the preoperative estimation and postoperative therapy of LUAD.

Actívatexto: Feasibility and Acceptability of a Mobile Intervention That Promotes Smoking Cessation and Physical Activity among Latinos.

The purpose of this study was to assess the feasibility and acceptability of a mobile intervention that promotes smoking cessation and physical activity among Latinos living in the United States. Twenty Latino adults who smoked and did not meet recommended levels of physical activity were recruited using community-based recruitment strategies. Participants received Actívatexto, a theory-based, culturally accommodated, 12-week text messaging intervention (available in English and Spanish) that promotes smoking cessation and physical activity. Actívatexto integrates four components: (i) a text messaging program, (ii) a wearable device, (iii) an online dashboard where the research team manages participants' incoming and outgoing data from both the text messaging program and wearable device, and (iv) nicotine replacement therapies (NRT). We assessed self-reported 7-day point prevalence smoking abstinence at month 3, weekly minutes of moderate to vigorous physical activity (MVPA), pharmacotherapy adherence, and satisfaction. At baseline, participants' mean age was 47.3 years old (SD 16.0), 55% of participants were female, and 60% indicated that Spanish was their language of preference. Seventy-five percent of participants smoked 1-10 cigarettes daily and 35% smoked their first cigarette within 5 minutes after waking up. At month 3, 14 participants (70%) self-reported 7-day point prevalence smoking abstinence (90% follow-up rate). Fitbit-assessed mean minutes of MVPA per week increased from 113 (SD 127; range: 0-399) at week 1 to 177 (SD 163; range: 0-513) at month 3 (P = 0.15). Sixteen participants (88.9%, 16/18) reported NRT use in the past 90 days. Most participants reported being extremely satisfied or satisfied with the intervention (88.9%, 16/18). SIGNIFICANCE: Actívatexto resulted in a noteworthy cessation rate at month 3 (70%), increased mean weekly minutes of MVPA, produced high use of NRT, and was well received by participants. Additional testing in a randomized clinical trial is warranted to assess the efficacy of the intervention.

Ventilation during COVID-19 in a school for students with intellectual and developmental disabilities (IDD).

BACKGROUND: This study examined the correlation of classroom ventilation (air exchanges per hour (ACH)) and exposure to CO2 ≥1,000 ppm with the incidence of SARS-CoV-2 over a 20-month period in a specialized school for students with intellectual and developmental disabilities (IDD). These students were at a higher risk of respiratory infection from SARS-CoV-2 due to challenges in tolerating mitigation measures (e.g. masking). One in-school measure proposed to help mitigate the risk of SARS-CoV-2 infection in schools is increased ventilation. METHODS: We established a community-engaged research partnership between the University of Rochester and the Mary Cariola Center school for students with IDD. Ambient CO2 levels were measured in 100 school rooms, and air changes per hour (ACH) were calculated. The number of SARS-CoV-2 cases for each room was collected over 20 months. RESULTS: 97% of rooms had an estimated ACH ≤4.0, with 7% having CO2 levels ≥2,000 ppm for up to 3 hours per school day. A statistically significant correlation was found between the time that a room had CO2 levels ≥1,000 ppm and SARS-CoV-2 PCR tests normalized to room occupancy, accounting for 43% of the variance. No statistically significant correlation was found for room ACH and per-room SARS-CoV-2 cases. Rooms with ventilation systems using MERV-13 filters had lower SARS-CoV-2-positive PCR counts. These findings led to ongoing efforts to upgrade the ventilation systems in this community-engaged research project. CONCLUSIONS: There was a statistically significant correlation between the total time of room CO2 concentrations ≥1,000 and SARS-CoV-2 cases in an IDD school. Merv-13 filters appear to decrease the incidence of SARS-CoV-2 infection. This research partnership identified areas for improving in-school ventilation.

Evaluation of left ventricular flow field changes after stress in patients with nonobstructive coronary artery disease using ultrasonic flow vector imaging.

Purpose: Vector flow mapping and treadmill exercise stress echocardiography were used to evaluate and explore changes in the left ventricular (LV) flow field of patients with nonobstructive coronary artery disease. Methods: Overall, 34 patients with nonobstructive (<50%) left anterior descending coronary artery stenosis (case group) and 36 patients with no coronary artery stenosis (control group) were included. Apical four-, three-, and two-chamber echocardiographic images were collected at rest and during early recovery from treadmill exercise. LV flow field, vortex area, and circulation (cir) changes were recorded in different phases: isovolumetric systole (S1), rapid ejection (S2), slow ejection (S3), isovolumetric diastole (D1), rapid filling (D2), slow filling (D3), and atrial systole (D4). Intra- and inter-group differences were compared before and after exercise loading. Results: The control and case groups demonstrated regular trends of eddy current formation and dissipation at rest and under stress. Compared with the control group, the case group had irregular streamline distributions. Abnormal vortices formed in the S1 and D3 apical segments and D1 left ventricular middle segment in the resting group. Compared with the control group, the resting group had decreased left ventricular S1 vortex areas and increased S3 vortex areas. The post-stress D1 and D3 vortex areas and D1 and D2 cir increased. Compared with at rest, after stress, the control group had decreased S1, S3, D2, and D3 vortex areas; increased S2, D1, D3, and D4 cir; and decreased D2 cir. After stress, the case group had decreased S3 and D2 vortex areas, increased D1 vortex areas, and increased S2, D1, D3, and D4 cir (P all < 0.001). Logistic regression and ROC curve analyses show that increased D1 vortex area after stress is an independent risk factor for stenosis in nonobstructive stenosis of coronary arteries (OR: 1.007, 95% CI: 1.005-1.010, P < 0.05). A D1 vortex area cutoff value of 82.26 had an AUC, sensitivity, and specificity of 0.67, 0.655, and 0.726, respectively. Conclusion: The resting left ventricular flow field changed in patients with nonobstructive left anterior descending coronary artery stenosis. Both groups had more disordered left ventricular blood flow after stress. The increased D1 vortex area after stress is an independent risk factor for mild coronary stenosis and may contribute to the assessment of nonobstructive coronary stenosis. VFM combined with treadmill stress is useful in evaluating left ventricular flow field changes in patients with nonobstructive coronary artery disease, which is valuable in the early evaluation of coronary heart disease.

Photodynamic application in diagnostic procedures and treatment of non-melanoma skin cancers.

OPINION STATEMENT: Skin tumors commonly seen in dermatology are involved in all layers of the skin and appendages. While biopsy of affected skin remains an essential method to confirm diagnosis and to predicate tumor prognosis, it has its limitations. Recently, photodynamic diagnosis (PDD) has demonstrated high sensitivity in detecting affected skin and mucosal tissues, providing valuable guidance for precision surgery to resect skin and mucosal tumors. In this review, we summarized the literatures concerning the applications of PDD in diagnostic process and treatment of skin and mucosal conditions such as actinic keratoses (AK), basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Bowen's disease (BD) and extramammary Paget's disease (EMPD). The findings suggest that PDD holds substantial promise for expanding clinical applications and deserves further research exploration.

Skin barrier-inflammatory pathway is a driver of the psoriasis-atopic dermatitis transition.

As chronic inflammatory conditions driven by immune dysregulation are influenced by genetics and environment factors, psoriasis and atopic dermatitis (AD) have traditionally been considered to be distinct diseases characterized by different T cell responses. Psoriasis, associated with type 17 helper T (Th17)-mediated inflammation, presents as well-defined scaly plaques with minimal pruritus. AD, primarily linked to Th2-mediated inflammation, presents with poorly defined erythema, dry skin, and intense itching. However, psoriasis and AD may overlap or transition into one another spontaneously, independent of biological agent usage. Emerging evidence suggests that defects in skin barrier-related molecules interact with the polarization of T cells, which forms a skin barrier-inflammatory loop with them. This loop contributes to the chronicity of the primary disease or the transition between psoriasis and AD. This review aimed to elucidate the mechanisms underlying skin barrier defects in driving the overlap between psoriasis and AD. In this review, the importance of repairing the skin barrier was underscored, and the significance of tailoring biologic treatments based on individual immune status instead of solely adhering to the treatment guidelines for AD or psoriasis was emphasized.

Mitochondria complex I deficiency in Candida albicans arrests the cell cycle at S phase through suppressive TOR and PKA pathways.

How mutations in mitochondrial electron transport chain (ETC) proteins impact the cell cycle of Candida albicans was investigated in this study. Using genetic null mutants targeting ETC complexes I (CI), III (CIII), and IV (CIV), the cell cycle stages (G0/G1, S phase, and G2/M) were analyzed via fluorescence-activated cell sorting (FACS). Four CI null mutants exhibited distinct alterations, including extended S phase, shortened G2/M population, and a reduction in cells size exceeding 10 µM. Conversely, CIII mutants showed an increased population in G1/G0 phase. Among four CI mutants, ndh51Δ/Δ and goa1Δ/Δ displayed aberrant cell cycle patterns correlated with previously reported cAMP/PKA downregulation. Specifically, nuo1Δ/Δ and nuo2Δ/Δ mutants exhibited increased transcription of RIM15, a central hub linking cell cycle with nutrient-dependent TOR1 and cAMP/PKA pathways and Snf1 aging pathway. These findings suggest that suppression of TOR1 and cAMP/PKA pathways or enhanced Snf1 disrupts cell cycle progression, influencing cell longevity and growth among CI mutants. Overall, our study highlights the intricate interplay between mitochondrial ETC, cell cycle, and signaling pathways.

Recruiting Latino young adults into a vaping cessation study via social media: Feasibility and cost analysis.

INTRODUCTION: This study aims to assess the feasibility and cost of recruiting young Latino adults (aged 18-25 years) to participate in a vaping cessation study via social media and to describe the baseline characteristics of participants enrolled via social media. METHODS: Paid advertisements were launched using the Meta Ads platform, which serves ads to users on Facebook and Instagram. Key measures of audience targeting included ages 18-25 years, all genders, and the following interests: 'electronic cigarettes', 'vape', 'Latin pop', and 'Latin music'. The advertisements invited young Latino adults to join a text messaging vaping cessation study. By clicking on the advertisements, interested individuals were directed to a website to fill in a contact form. The study team contacted individuals who filled in the form, assessed them for study eligibility, and, if eligible, enrolled them in the study. RESULTS: A total of 164 individuals completed the contact form, and 26 were successfully enrolled in the study. The enrollment efficiency ratio was 15.9% (26/164). The cost per enrollment was US$94.14. The participants' mean age was 22.7 years (SD=1.6). Half of the participants (50%) were male, 38.5% were female, and 11.5% were gender non-conforming/non-binary. Two-thirds of the participants (69.2%) were born in the US, 23.1% in Puerto Rico, and 7.7% in Mexico. Eight participants (30.7%) selected Spanish as their language of preference. In terms of the type of vaping device, 16 participants (61.5%) indicated using disposables, 6 (23.1%) cartridges/pods, and 4 (15.4%) tanks/refillable. Sixteen participants (61.5%) reported using marijuana in e-cigarettes. Six participants (23.1%) had high e-cigarette dependence. Twenty participants (76.9%) had attempted to quit e-cigarettes in the past year. CONCLUSIONS: It is feasible to recruit young Latino adults for a vaping cessation study via social media. Social media offers a relatively low-cost approach to recruiting a diverse sample of Latino young adults who vape.

Social Network Analysis of e-Cigarette-Related Social Media Influencers on Twitter/X: Observational Study.

BACKGROUND: An e-cigarette uses a battery to heat a liquid that generates an aerosol for consumers to inhale. e-Cigarette use (vaping) has been associated with respiratory disease, cardiovascular disease, and cognitive functions. Recently, vaping has become increasingly popular, especially among youth and young adults. OBJECTIVE: The aim of this study was to understand the social networks of Twitter (now rebranded as X) influencers related to e-cigarettes through social network analysis. METHODS: Through the Twitter streaming application programming interface, we identified 3,617,766 unique Twitter accounts posting e-cigarette-related tweets from May 3, 2021, to June 10, 2022. Among these, we identified 33 e-cigarette influencers. The followers of these influencers were grouped according to whether or not they post about e-cigarettes themselves; specifically, the former group was defined as having posted at least five e-cigarette-related tweets in the past year, whereas the latter group was defined as followers that had not posted any e-cigarette-related tweets in the past 3 years. We randomly sampled 100 user accounts among each group of e-cigarette influencer followers and created corresponding social networks for each e-cigarette influencer. We compared various network measures (eg, clustering coefficient) between the networks of the two follower groups. RESULTS: Major topics from e-cigarette-related tweets posted by the 33 e-cigarette influencers included advocating against vaping policy (48.0%), vaping as a method to quit smoking (28.0%), and vaping product promotion (24.0%). The follower networks of these 33 influencers showed more connections for those who also post about e-cigarettes than for followers who do not post about e-cigarettes, with significantly higher clustering coefficients for the former group (0.398 vs 0.098; P=.005). Further, networks of followers who post about e-cigarettes exhibited substantially more incoming and outgoing connections than those of followers who do not post about e-cigarettes, with significantly higher in-degree (0.273 vs 0.084; P=.02), closeness (0.452 vs 0.137; P=.04), betweenness (0.036 vs 0.008; P=.001), and out-of-degree (0.097 vs 0.014; P=.02) centrality values. The followers who post about e-cigarettes also had a significantly (P<.001) higher number of followers (n=322) than that of followers who do not post about e-cigarettes (n=201). The number of tweets in the networks of followers who post about e-cigarettes was significantly higher than that in the networks of followers who do not post about e-cigarettes (93 vs 43; P<.001). Two major topics discussed in the networks of followers who post about e-cigarettes included promoting e-cigarette products or vaping activity (55.7%) and vaping being a help for smoking cessation and harm reduction (44.3%). CONCLUSIONS: Followers of e-cigarette influencers who also post about e-cigarettes have more closely connected networks than those of followers who do not themselves post about e-cigarettes. These findings provide a potentially practical intervention approach for future antivaping campaigns.

Vaping: Public Health, Social Media, and Toxicity.

This viewpoint aims to provide a comprehensive understanding of vaping from various perspectives that contribute to the invention, development, spread, and consequences of e-cigarette products and vaping. Our analysis showed that the specific characteristics of e-cigarette products as well as marketing strategies, especially social media marketing, fostered the spread of vaping and the subsequent effects on human health and toxicity. We analyzed the components of e-cigarette devices and e-liquids, including the latest variants whose impacts were often overlooked. The different forms of nicotine, including salts and freebase nicotine, tobacco-derived nicotine, tobacco-free nicotine, and cooling agents (WS3 and WS23), have brought more choices for vapers along with more ways for e-cigarette manufacturers to advertise false understandings and present a greater threat to vapers' health. Our work emphasized the products of brands that have gained significant influence recently, which are contributing to severe public health issues. On the other hand, we also discussed in detail the toxicity of e-liquid components and proposed a toxicity mechanism. We also noticed that nicotine and other chemicals in e-liquids promote each other's negative effects through the oxidative stress and inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, a mechanism leading to pulmonary symptoms and addiction. The impact of government regulations on the products themselves, including flavor bans or regulations, has been limited. Therefore, we proposed further interventions or harm reduction strategies from a public health perspective.

Radioactivity of inert construction and demolition waste from Hong Kong and environmental assessment for marine trial reclamation in Guanghai Bay.

Inert construction and demolition waste from Hong Kong (HK public fills) has been used for marine trial reclamation in the Guanghai Bay (GHWT) of the Chinese Mainland. However, an environmental assessment of HK public fills is necessary due to higher radioactivity in HK soils than typical global levels. Here, radiation dose rate, gamma radionuclides and gross beta of HK public fills were analyzed. The origin information was explored using natural primordial radionuclides as fingerprints. Our data show that radiation dose rate of HK public fills before disposal was 0.14-0.54 (0.33 ±â€¯0.03) µSv/h (n = 16,722 data with 2787 ships) in 2014, which is less than the GHWT background. Monthly detection of 238U, 226Ra, 210Pb, 232Th, 228Th, 40K, and gross beta in HK public fills was conducted on three random ships. Their specific activities were <6.27-155.5, 58.7-98.7, <7.83-238.2,97.9-168.6, 87.1-136.0, 463.1-1,018, and 1047-1658 Bq/kgDW, respectively. These results suggest that the radioactivity levels of HK public fills are essentially the same as the GHWT background. The study assessed potential risks using various indices icluding Raeq (Radium equivalent activity), Hex (External radiation hazard index), Hin (Internal radiation hazard index), Iγ (Gamma index), AUI (Activity utilization index), AUI (Activity utilization index), E (Annual effective dose), AGDE (Annual gonadal dose equivalent), RLI (Representative level index), Din (Indoor air absorbed dose rate), Dout (Outdoor air absorbed dose rate), and ELCR (Excess lifetime cancer risk). The study suggests that HK public fills should be used for the trial reclamation rather than building-house materials. This provides valuable insights for the resource utilization and minimizing environmental pollution of HK public fills. The aim is to offer fundamental technical assistance for future waste resource utilization, ecological protection, and restoration in the Guangdong-Hong Kong-Macao Greater Bay Area.

Fulvic Acid Promotes Legume-Rhizobium Symbiosis by Stimulating Endogenous Flavonoids Synthesis and Secretion.

Fulvic acid (FA) promotes symbiosis between legumes and rhizobia. To elucidate from the aspect of symbiosis, the effects of root irrigation of water-soluble humic materials (WSHM) or foliar spraying of its highly active component, FA, on soybean root exudates and on rhizosphere microorganisms were investigated. As a result, WSHM/FA treatments significantly altered root exudate metabolite composition, and isoflavonoids were identified as key contributors in both treatments compared to the control. Increased expression of genes related to the isoflavonoid biosynthesis were validated by RT-qPCR in both treatments, which notably elevated the synthesis of symbiotic signals genistein, daidzin, coumestrol, and biochanin A. Moreover, the WSHM/FA treatments induced a change in rhizosphere microbial community, coupled with an increase in the relative abundance of rhizobia. Our findings showed that WSHM/FA promotes symbiosis by stimulating the endogenous flavonoid synthesis and leads to rhizobia accumulation in the rhizosphere. This study provides new insights into mechanisms underlying the FA-mediated promotion of symbiosis.

Adult classic Bartter syndrome: a case report with 5-year follow-up and literature review.

Bartter syndrome (BS) is a rare, inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism, hypokalemia, hypochloremia, metabolic alkalosis, and low-to-normal blood pressure. Classic BS, or BS Type 3, the most common subtype in the Asian population, is caused by a molecular defect in ClC-Kb, a voltage-gated chloride channel in renal tubules, due to CLCNKB gene mutation. Because the onset of BS is more common in children than in adults, the diagnosis, treatment outcomes, genotype/phenotype association, and follow-up of adult-onset BS Type 3 are limited. This case report describes the findings in a 20-year-old man who was admitted with hypokalemic paralysis, with clinical manifestations were similar to those of Gitelman syndrome (GS); however, the patient was later diagnosed to have BS Type 3 through genetic testing (NM_000085.4 (CLCNKB): c.1052G>T). A literature review showed that no homozygous mutations have been reported to date. After 5 years of treatment and follow-up, we found that this genotype requires high levels of potassium and is prone to urinary protein and metabolic syndrome. Distinguishing adult-onset BS from GS is challenging in clinical practice. However, genetic diagnosis can help solve this problem effectively, and genotypes play a guiding role in treatment planning.

A Cocktail of Lipid Nanoparticle-mRNA Vaccines Broaden Immune Responses against ß-Coronaviruses in a Murine Model.

Severe acute respiratory syndrome (SARS)-coronavirus (CoV), Middle Eastern respiratory syndrome (MERS)-CoV, and SARS-CoV-2 have seriously threatened human life in the 21st century. Emerging and re-emerging ß-coronaviruses after the coronavirus disease 2019 (COVID-19) epidemic remain possible highly pathogenic agents that can endanger human health. Thus, pan-ß-coronavirus vaccine strategies to combat the upcoming dangers are urgently needed. In this study, four LNP-mRNA vaccines, named O, D, S, and M, targeting the spike protein of SARS-CoV-2 Omicron, Delta, SARS-CoV, and MERS-CoV, respectively, were synthesized and characterized for purity and integrity. All four LNP-mRNAs induced effective cellular and humoral immune responses against the corresponding spike protein antigens in mice. Furthermore, LNP-mRNA S and D induced neutralizing antibodies against SARS-CoV and SARS-CoV-2, which failed to cross-react with MERS-CoV. Subsequent evaluation of sequential and cocktail immunizations with LNP-mRNA O, D, S, and M effectively elicited broad immunity against SARS-CoV-2 variants, SARS-CoV, and MERS-CoV. A direct comparison of the sequential with cocktail regimens indicated that the cocktail vaccination strategy induced more potent neutralizing antibodies and T-cell responses against heterotypic viruses as well as broader antibody activity against pan-ß-coronaviruses. Overall, these results present a potential pan-ß-coronavirus vaccine strategy for improved preparedness prior to future coronavirus threats.

Divergent mitochondrial responses and metabolic signal pathways secure the azole resistance in Crabtree-positive and negative Candida species.

Azole drugs are the main therapeutic drugs for invasive fungal infections. However, azole-resistant strains appear repeatedly in the environment, posing a major threat to human health. Several reports have shown that mitochondria are associated with the virulence of pathogenic fungi. However, there are few studies on the mechanisms of mitochondria-mediated azoles resistance. Here, we first performed mitochondrial proteomic analysis on multiple Candida species (Candida albicans, Nakaseomyces glabrata, Pichia kudriavzevii, and Candida auris) and analyzed the differentially expressed mitochondrial proteins (DEMPs) between azole-sensitive and azole-resistant Candida species. Subsequently, we performed Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene ontology analysis, and protein-protein interaction network analysis of DEMPs. Our results showed that a total of 417, 165, and 25 DEMPs were identified in resistant C. albicans, N. glabrata, and C. auris, respectively. These DEMPs were enriched in ribosomal biogenesis at cytosol and mitochondria, tricarboxylic acid cycle, glycolysis, transporters, ergosterol, and cell wall mannan biosynthesis. The high activations of these cellular activities, found in C. albicans and C. auris (at low scale), were mostly opposite to those observed in two fermenter species-N. glabrata and P. kudriavzevii. Several transcription factors including Rtg3 were highly produced in resistant C. albicans that experienced a complex I activation of mitochondrial electron transport chain (ETC). The reduction of mitochondrial-related activities and complex IV/V of ETC in N. glabrata and P. kudriavzevii was companying with the reduced proteins of Tor1, Hog1, and Snf1/Snf4.IMPORTANCECandida spp. are common organisms that cause a variety of invasive diseases. However, Candida spp. are resistant to azoles, which hinders antifungal therapy. Exploring the drug-resistance mechanism of pathogenic Candida spp. will help improve the prevention and control strategy and discover new targets. Mitochondria, as an important organelle in eukaryotic cells, are closely related to a variety of cellular activities. However, the role of mitochondrial proteins in mediating azole resistance in Candida spp. has not been elucidated. Here, we analyzed the mitochondrial proteins and signaling pathways that mediate azole resistance in Candida spp. to provide ideas and references for solving the problem of azole resistance. Our work may offer new insights into the connection between mitochondria and azoles resistance in pathogenic fungi and highlight the potential clinical value of mitochondrial proteins in the treatment of invasive fungal infections.

The economic effect of financial compensation in China's healthcare system: comprehensive insights regarding supply and demand factors.

OBJECTIVES: We aim to analyse the effects of government subsidies on residents' health and healthcare expenditure from the perspectives of supply and demand. DATA AND METHODS: According to the regional division adopted in the data query system of the National Bureau of Statistics, this study divides 31 provinces and cities into three regions: eastern, central, and western. The data used are from public databases, such as the "China Statistical Yearbook," "China Health Statistical Yearbook," and "Government Final Account Report". In this study, mathematical model derivation is used to construct a fixed effects model, and an empirical study based on cross-sectional data and general linear regression is conducted. To prevent endogeneity issues, this study introduces instrumental variables and uses 2SLS regression to further analyse the output results. RESULTS: For every 1% increase in supplementary funding on the supply side, the perinatal mortality rate decreases by 1.765%, while for every 1% increase in financial compensation on the demand side, per capita outpatient expenses increase by 0.225% and per capita hospitalization expenses increase by 0.196%. Regarding medical resources, for every 1% increase in the number of beds per 1,000 people, per capita hospitalization expenses decrease by 0.099%. In the central and eastern regions, where economic levels are higher, supply-side government funding is more effective than demand-side funding. In contrast, demand-side funding is more effective in the western region. CONCLUSIONS: The roles of multiple influencing factors and significant regional heterogeneity are clarified. Increasing financial compensation to providers positively impacts perinatal mortality but leads to higher per capita outpatient and hospital expenditures. Finally, this study provides targeted policy recommendations and solid theoretical support for policymakers.

MicroRNA-7 deficiency ameliorates d-galactose-induced aging in mice by regulating senescence of Kupffer cells.

Aging is intricately linked to immune system dysfunction. Recent studies have highlighted the biological function of microRNA-7 (miR-7) as a novel regulator of immune cell function and related diseases. However, the potential role of miR-7 in aging remains unexplored. Here, we investigated the contribution of miR-7 to d-gal-induced aging in mice, focusing on its regulation of senescent Kupffer cells. Our findings revealed that miR-7 deficiency significantly ameliorated the aging process, characterized by enhanced CD4+ T-cell activation. However, the adoptive transfer of miR-7-deficient CD4+ T cells failed to improve the age-related phenotype. Further analysis showed that miR-7 deficiency significantly reduced IL-1ß production in liver tissue, and inhibiting IL-1ß in vivo slowed down the aging process in mice. Notably, IL-1ß is mainly produced by senescent Kupffer cells in the liver tissue of aging mice, and miR-7 expression was significantly up-regulated in these cells. Mechanistically, KLF4, a target of miR-7, was down-regulated in senescent Kupffer cells in aging mouse model. Furthermore, miR-7 deficiency also modulated the NF-κB activation and IL-1ß production in senescent Kupffer cells through KLF4. In conclusion, our findings unveil the role of miR-7 in d-gal-induced aging in mice, highlighting its regulation of KLF4/NF-κB/IL-1ß pathways in senescent Kupffer cells. This research may enhance our understanding of miRNA-based aging immune cells and offer new avenues for new intervention strategies in aging process.

Public perceptions of synthetic cooling agents in electronic cigarettes on Twitter.

Amid a potential menthol ban, electronic cigarette (e-cigarette) companies are incorporating synthetic cooling agents like WS-3 and WS-23 to replicate menthol/mint sensations. This study examines public views on synthetic cooling agents in e-cigarettes via Twitter data. From May 2021 to March 2023, we used Twitter Streaming Application Programming Interface (API), to collect tweets related to synthetic cooling agents with keywords such as 'WS-23,' 'ice,' and 'frozen.' The deep learning RoBERTa (Robustly Optimized BERT-Pretraining Approach) model that can be optimized for contextual language understanding was used to classify attitudes expressed in tweets about synthetic cooling agents and identify e-cigarette users. The BERTopic (a topic modeling technique that leverages Bidirectional Encoder Representations from Transformers) deep-learning model, specializing in extracting and clustering topics from large texts, identified major topics of positive and negative tweets. Two proportion Z-tests were used to compare the proportions of positive and negative attitudes between e-cigarette users (vapers) and non-e-cigarette-users (non-vapers). Of 6,940,065 e-cigarettes-related tweets, 5,788 were non-commercial tweets related to synthetic cooling agents. The longitudinal trend analysis showed a clear upward trend in discussions. Vapers posted most of the tweets (73.05%, 4,228/5,788). Nearly half (47.87%, 2,771/5,788) held a positive attitude toward synthetic cooling agents, which is significantly higher than those with a negative attitude (19.92%,1,153/5,788) with a P-value < 0.0001. The likelihood of vapers expressing positive attitudes (60.17%, 2,544/4,228) was significantly higher (P < 0.0001) than that of non-vapers (14.55%, 227/1,560). Conversely, negative attitudes from non-vapers (30%, 468/1,560) were significantly (P < 0.0001) higher than vapers (16.2%, 685/4,228). Prevalent topics from positive tweets included "enjoyment of specific vape flavors," "preference for lush ice vapes," and "liking of minty/icy feelings." Major topics from negative tweets included "disliking certain vape flavors" and "dislike of others vaping around them." On Twitter, vapers are more likely to have a positive attitude toward synthetic cooling agents than non-vapers. Our study provides important insights into how the public perceives synthetic cooling agents in e-cigarettes. These insights are crucial for shaping future U.S. Food and Drug Administration (FDA) regulations aimed at safeguarding public health.