Histone-like transcription factor Hfl1p in Candida albicans harmonizes nuclear and mitochondrial genomic network in regulation of energy metabolism and filamentation development.

Candida albicans is an opportunistic fungal pathogen known for surviving in various nutrient-limited conditions within the host and causing infections. Our prior research revealed that Hfl1p, an archaeal histone-like or Hap5-like protein, is linked to mitochondrial ATP generation and yeast-hyphae morphogenesis. However, the specific roles of Hfl1p in these virulence behaviours, through its function in the CBF/NF-Y complex or as a DNA polymerase II subunit, remain unclear. This study explores Hfl1p's diverse functions in energy metabolism and morphogenesis. By combining proteomic analysis and phenotypic evaluations of the hfl1Δ/hfl1Δ mutant with ChIP data, we found that Hfl1p significantly impacts mitochondrial DNA-encoded CI subunits, the tricarboxylic acid (TCA) cycle, and morphogenetic pathways. This influence occurs either independently or alongside other transcription factors recognizing a conserved DNA motif (TAXXTAATTA). These findings emphasize Hfl1p's critical role in linking carbon metabolism and mitochondrial respiration to the yeast-to-filamentous form transition, enhancing our understanding of C. albicans' metabolic adaptability during morphological transition, an important pathogenic trait of this fungus. This could help identify therapeutic targets by disrupting the relationship between energy metabolism and cell morphology in C. albicans.

The association of psoriasis with composite dietary antioxidant index and its components: a cross-sectional study from the National Health and Nutrition Examination Survey.

BACKGROUND: Psoriasis is a chronic inflammatory skin disorder associated with various comorbidities. The role of nutrition and dietary antioxidants in psoriasis management has gained attention. The Composite Dietary Antioxidant Index (CDAI) quantifies overall dietary antioxidant intake, but its association with psoriasis remains unclear. This study aimed to investigate the association between the CDAI and psoriasis, as well as the relationship between individual components of CDAI and psoriasis risk. METHODS: Data from the US National Health and Nutrition Examination Survey (NHANES) were analyzed. Baseline characteristics, CDAI scores, and psoriasis status were assessed. Multivariable logistic regression and restricted cubic splines were employed to analyze the association. RESULTS: The study included 23,311 participants, with 621 diagnosed with psoriasis. Higher CDAI scores were associated with a lower odds ratio (OR) of psoriasis occurrence (OR = 0.72, 95% CI 0.56-0.92, P = 0.009 in Model 3). Vitamin E intake exhibited an inverse correlation with psoriasis risk (OR = 0.76, 95% CI 0.60-0.96, P = 0.039 in Model 3). Other CDAI components did not show significant associations with psoriasis. CONCLUSION: This study demonstrates a significant inverse association between CDAI and psoriasis, indicating that higher dietary antioxidant intake is associated with a reduced risk of psoriasis. Specifically, higher vitamin E intake was associated with a lower likelihood of psoriasis. These findings underscore the potential role of dietary antioxidants in psoriasis management. Further research is warranted to elucidate the underlying mechanisms and explore targeted dietary interventions.

Chinese expert consensus on management of antifungal-resistant dermatophytoses (2024 edition).

Antifungal-resistant dermatophytes (ARD) infection is a hotspot issue in clinical microbiology and the dermatology field. Trichophyton indotineae as the dominant species of dermatophyte with terbinafine-resistance or multidrug resistance, is easy to be missed detection clinically, which brings severe challenges to diagnosis and treatment. ARD infection cases have emerged in China, and it predicts a risk of transmission among human. Based on the existing medical evidence and research data, the Mycology Group of Combination of Traditional and Western Medicine Dermatology and Chinese Antifungal⁃Resistant Dermatophytoses Expert Consensus Group organized experts to make consensus on the management of the infection. Here, the consensus formulated diagnosis and treatment recommendations, to raise attention to dermatophytes drug resistance problem, and expect to provide reference information for the clinical diagnosis, treatment, prevention and control.

Comparative Evaluation of Candida Species-Specific T-Cell Immune Response in Human Peripheral Blood Mononuclear Cells.

Non-albicans Candida (NAC) species are increasingly recognized as significant contributors to candidemia infections; however, relatively less is known about the immune responses induced by these species. In this study, we compared the cytokine production ability of human peripheral blood mononuclear cells (PBMCs) upon stimulation with different Candida species (Candida spp.). We measured secreted cytokines using ELISA and checked the functional profiles of T-cell responses using multicolor flow cytometry. Although there was a differential expression of cytokines against Candida spp., significant difference were observed in the levels of IFN-γ, TNF-α, IL-10, IL-12p40, and IL-23 (p < 0.05) between Candida spp. A significant difference was observed between C. albicans and C. glabrata (p = 0.026) in the levels of TNF-α. C. glabrata showed significant differences compared to C. albicans, C. parapsilosis, and C. krusei in the levels of IL-10 (p values of 0.02, 0.04, and 0.01, respectively). Despite the percentages of CD4+ and CD8+ expressing Th1, Th2, and Th17 cytokines being higher in stimulated PBMCs, none of the Candida spp. showed significant differences. The levels of secreted IL-17A and IL-23 were consistently lower in Candida spp. regardless of the stimulus used. Here, we showed the differential regulation of Th1, Th2, and Th17 during Candida spp. stimulation of the immune system ex vivo. Additionally, our findings suggest that C. albicans elicits an IFN-γ response, whereas C. glabrata promotes IL-10 cellular responses, but this warrants additional studies to conclude this association. This investigation holds the potential to advance our comprehension of the distinct immune responses induced by Candida spp., with probable implications in designing antifungal immunotherapeutics.

Dual-wavelength dye laser combined with betamethasone injection for treatment of keloids: protocol of a randomised controlled trial.

INTRODUCTION: Keloids, benign fibroproliferative tumours characterised by excessive fibroblast proliferation and over-deposition of extracellular matrix, pose a therapeutic challenge with high recurrence rates. Betamethasone (diprospan) injection (BI) is one of the most common non-invasive therapies for keloids. Pulsed dye laser (PDL) has the function of closing microvessels, which may become one of the auxiliary treatment methods of BI and may enhance its curative effect. Some studies suggest that the combination of a dual-wavelength dye laser (DWL) and BI may offer superior efficacy. This randomised controlled trial aims to evaluate whether the combined therapy of DWL+BI outperforms BI alone in treating keloids. METHODS AND ANALYSIS: This single-centre, parallel positive control, randomised trial evaluates the efficacy and safety of DWL (585 nm PDL+1064 nm neodymium-doped yttrium aluminium garnet) combined with BI for keloid treatment. Enrolling 66 adult patients, participants are randomised into DWL+BI or BI groups in a 1:1 ratio. Over 12 weeks, each group undergoes four treatment sessions, ensuring blinding for outcome assessors. Data collection occurs at multiple time points (4, 12, 24 and 52 weeks), with primary outcomes assessing the Vancouver Scar Scale (VSS) improvement rate 24 weeks after the last intervention. Secondary outcomes include VSS improvement rates, changes in keloid volume, changes in relative perfusion index measured by laser speckle contrast imaging, Patient and Observer Scar Assessment Scale results and patient satisfaction. Safety assessments include vital signs, laboratory tests, pregnancy tests and self-reports of adverse reactions. ETHICS AND DISSEMINATION: The results will be presented in peer-reviewed journals and at international conferences. This study is approved by the Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Register (ChiCTR2400080148).

Comparative Proteomics Analysis Reveals Distinct Molecular Phenotype and Biomarkers in Patients with Erythrodermic Atopic Dermatitis and Erythrodermic Psoriasis.

Erythrodermic atopic dermatitis (EAD) and erythrodermic psoriasis (EP) are rare yet debilitating inflammatory skin disorders that propose challenges in diagnosis and discovering effective therapeutic targets. Despite their clinical and histological similarities, the underlying molecular mechanisms and systemic biomarkers of these diseases are substantially unclear. In this study, we sought to investigate the differential serum proteome of EP and EAD patients and identify biomarkers for these two subtypes of erythroderma. We recruited 14 EAD patients, 14 EP patients and 14 healthy controls. Serum samples were collected and analyzed using the Olink high-throughput platform to assess the levels of 269 inflammation-/immune response-/cardiovascular-related biomarkers. Both EAD and EP patients exhibited enhanced immune activation and dysregulated cardiovascular profiles compared to healthy controls. EAD demonstrated a more pronounced inflammation tone, characterized by Th1/Th2/Th22/IL-1-dominant patterns, as well as increased TNF superfamily, Th17, and apoptosis markers. Conversely, EP displayed inflammation with Th1/Th17/TNF-skewing and mild Th2 upregulation, along with notable increases in epidermal-development markers. Disease severity in EAD was strongly correlated with apoptosis/Th2 markers, while correlated with Th17 markers in EP. Furthermore, a panel of eight markers (IL-17A/IL-17C/PI3/CCL20/SH2D1A/SIRT2/DFFA/IL-13) was identified that effectively discriminated between EP and EAD, with an Area Under the Curve greater than 0.8. Our study comprehensively characterizes the circulating molecular profiles in EAD and EP patients, providing insights into the similarities and complexities of their inflammation phenotypes. The identified serum biomarkers have the potential to differentiate between EP and EAD, which could aid in the diagnosis and guiding tailored therapeutics.

Coexistence of Malassezia Species and Microsporum canis in the Lesions of Adult with Tinea Capitis.

Tinea capitis, primarily caused by dermatophytes such as Trichophyton and Microsporum species, is a superficial fungal infection affecting the scalp and hair, commonly observed in prepubertal children but rare in adults. Here we report a unique case of an adult female with tinea capitis presenting as diffused alopecia and erythema inflammation on the scalp's apex, mimicking seborrheic dermatitis. Examination of the hair and scalp using fluorescence microscopy and fungal culture identified the presence of hyphae from Malassezia globosa, Malassezia furfur and Microsporum canis. The patient underwent with oral antifungal treatment for 3 months, resulting in the resolution of the rash and subsequent hair regrowth, with no recurrence during 6-month follow-up. In vitro co-culture experiments of Microsporum canis and Malassezia (both Malassezia globose and Malassezia furfur) revealed that Malassezia appears to facilitate Microsporum canis growth, while the reverse was not observed. This data suggests that Malassezia's use of long-chain fatty acids by might reduce its antibacterial effect, potentially aiding adult tinea capitis development caused by Microsporum canis.

Association between untreated and treated blood pressure levels and cognitive decline in community-dwelling middle-aged and older adults in China: a longitudinal study.

BACKGROUND: Optimal blood pressure (BP) levels to reduce the long-term risk of cognitive decline remains controversial. We aimed to investigate the association between BP and anti-hypertensive treatment status with cognitive decline in older adults. METHODS: This study used data from the China Health and Retirement Longitudinal Study. Cognitive function was assessed at year 2011, 2013, 2015, and 2018. Global cognitive Z-score was calculated as the average score of episodic memory and mental intactness. BP were measured at the first and second wave. Pulse pressure (PP) was calculated as systolic BP (SBP) minus diastolic BP. Cumulative BP was calculated as the area under the curve using BP measurements from 2011 to 2013. Linear mixed models were used to assess the longitudinal association between BP-related measurements and cognitive decline. RESULTS: We included 11,671 participants (47.3% men and mean age 58.6 years). Individual with BP > 140/90 mm Hg or taking anti-hypertensive medication were independently associated with accelerated cognitive decline (ß=-0.014, 95% CI: -0.020 to -0.007). Individuals with anti-hypertensive medication use, but with controlled SBP to less than 120 mm Hg did not have a significantly increased risk of cognitive decline compared with normotension (ß=-0.003, 95% CI: -0.021 to 0.014). Individuals on anti-hypertensive treatment with PP of more than 70 mm Hg had a significantly higher risk of cognitive decline (ß=-0.033, 95% CI: -0.045 to -0.020). Regardless of anti-hypertensive treatment status, both elevated baseline and cumulative SBP and PP were found to be independently associated with accelerated cognitive decline. CONCLUSIONS: Cumulatively elevated SBP, PP and uncontrolled BP were associated with subsequent cognitive decline. Effectively controlling BP with anti-hypertensive treatment may be able to preserve cognitive decline in older adults.

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.

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.

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.

Progress in molecular diagnosis and treatment of chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections with Candida of the skin, nails, and mucous membrane. It is a rare and severe disease resulting from autoimmune defects or immune dysregulations. Nonetheless, the diagnosis and treatment of CMC still pose significant challenges. Erroneous or delayed diagnoses remain prevalent, while the long-term utility of traditional antifungals often elicits adverse reactions and promotes the development of acquired resistance. Furthermore, disease relapse can occur during treatment with traditional antifungals. In this review, we delineate the advancements in molecular diagnostic and therapeutic approaches to CMC. Genetic and biomolecular analyses are increasingly employed as adjuncts to clinical manifestations and fungal examinations for accurate diagnosis. Simultaneously, a range of therapeutic interventions, including Janus kinase (JAK) inhibitors, hematopoietic stem cell transplantation (HSCT), cytokines therapy, novel antifungal agents, and histone deacetylase (HDAC) inhibitors, have been integrated into clinical practice. We aim to explore insights into early confirmation of CMC as well as novel therapeutic options for these patients.

Proteome-Wide Analysis of Lysine 2-Hydroxyisobutyrylation in Aspergillus fumigatus.

Aspergillus fumigatus is the significant causative agent in cases of invasive aspergillosis, leading to a high mortality rate in immunocompromised patients. A comprehensive understanding of its growth patterns and metabolic processes within the host is a critical prerequisite for the development of effective antifungal strategies. Lysine 2-hydroxyisobutyrylation (Khib) is a highly conserved protein posttranslational modifications (PTM) found in various organisms. In this study, we investigate the biological impact of Khib in A. fumigatus. Using a combination of antibody enrichment with the conventional LC-MS/MS method, the pattern of Khib-modification in proteins and their respective sites were analyzed in a wild type strain of A. fumigatus. Our findings revealed 3494 Khib-modified proteins with a total of 18,091 modified sites in this strain. Functional enrichment analysis indicated that these Khib-modified proteins participate in a diverse range of cellular functions, spanning various subcellular locations such as ribosome biosynthesis, protein synthesis and nucleocytoplasmic transport. Notably, when compared with other reported eukaryotes, A. fumigatus exhibited consistently higher numbers of Khib-modified proteins, suggesting the potential significance of this modification in this organism. An interesting observation is the prevalence of Khib modifications in most enzymes involved in the ergosterol synthesis pathway. The insights gathered from this study provide new avenue for studying PTM-associated mechanisms in fungal growth and offer potential implication for antifungal drug development.

Prior selection of itraconazole in the treatment of recalcitrant Trichophyton indotineae infection: Real-world results from retrospective analysis.

BACKGROUND: The number of terbinafine-resistant Trichophyton indotineae is increasing in recent years while the treatment is still a matter to discuss. OBJECTIVES: To explore the best therapeutic approach, we present real-world treatment of T. indotineae infection by analysing publicly available data. METHODS: We have reviewed all published articles, mainly including case reports and case series, on the drug-resistant T. mentagrophytes complex by using the key search terms to search the databases. RESULTS: We enrolled 25 articles from 14 countries, including 203 times of treatment information for 113 patients. The cure rate of itraconazole 200 mg per day at the fourth, eighth and the twelfth week were 27.27%, 48.48% and 54.55%, respectively, which was significantly higher than terbinafine 250 mg per day (8.77%, 24.56% and 28.07%) and even 500 mg/d terbinafine. Griseofulvin 500-1000 mg for 2-6 months may be effective while fluconazole had no record of successful treatment. Voriconazole and ravuconazole had potential therapeutic efficacy. Topical therapy alone showed limited therapeutic efficacy, but the combination with oral antifungals can be alternative. CONCLUSION: Oral itraconazole 200 mg per day for 4-8 weeks was the most effective treatment out of these commonly used antifungal drugs, and can be prior selection.

Structural visualization of transcription initiation in action.

Transcription initiation is a complex process, and its mechanism is incompletely understood. We determined the structures of de novo transcribing complexes TC2 to TC17 with RNA polymerase II halted on G-less promoters when nascent RNAs reach 2 to 17 nucleotides in length, respectively. Connecting these structures generated a movie and a working model. As initially synthesized RNA grows, general transcription factors (GTFs) remain bound to the promoter and the transcription bubble expands. Nucleoside triphosphate (NTP)-driven RNA-DNA translocation and template-strand accumulation in a nearly sealed channel may promote the transition from initially transcribing complexes (ITCs) (TC2 to TC9) to early elongation complexes (EECs) (TC10 to TC17). Our study shows dynamic processes of transcription initiation and reveals why ITCs require GTFs and bubble expansion for initial RNA synthesis, whereas EECs need GTF dissociation from the promoter and bubble collapse for promoter escape.

Associations of dietary copper intake with cardiovascular disease and mortality: findings from the Chinese Perspective Urban and Rural Epidemiology (PURE-China) Study.

BACKGROUND: Previous in vitro and animal experiments have shown that copper plays an important role in cardiovascular health. Dietary copper is the main source of copper in the human body and the association between dietary copper and cardiovascular disease remains unclear. Our study aimed to investigate the associations of dietary copper intake with the risk of major cardiovascular disease incidence, cardiovascular disease mortality, and all-cause mortality in Chinese adults. METHODS: Our study is based on Prospective Urban Rural Epidemiology China (PURE-China), a large prospective cohort study of 47 931 individuals aged 35-70 years from 12 provinces in China. Dietary intake was recorded using a validated semi-quantitative food frequency questionnaire designed specifically for the Chinese population. The daily intake of copper was obtained by multiplying the daily food intake with the nutrient content provided in the Chinese Food Composition Table (2002). Cox frailty proportional hazards models were developed to evaluate the association between dietary copper intake with mortality, major cardiovascular disease events, and their composite. RESULTS: A total of 45 101 participants (mean age: 51.1 ± 9.7 years old) with complete information were included in the current study. The mean dietary copper intake was 2.6 ± 1.1 mg/d. During the 482 833 person-years of follow-up, 2 644(5.9%) participants died, 4 012(8.9%) developed new cardiovascular diseases, and 5 608(12.4%) participants experienced the composite endpoint. Compared with those in the first and second quartile of dietary copper intake, individuals in the third and fourth quantile had higher risk of composite outcomes, all-cause death, cardiovascular disease death, major cardiovascular disease and stroke occurrences. The associations remained similar in the subgroup and sensitivity analyses. CONCLUSIONS: Our findings demonstrated that excessive dietary copper intake was associated with higher risks of death and cardiovascular diseases in Chinese adults. Further studies in populations with different dietary characteristics are needed to obtain dose-response relationships and to refine global dietary recommendations.

Socioeconomic disparity in mortality and the burden of cardiovascular disease: analysis of the Prospective Urban Rural Epidemiology (PURE)-China cohort study.

BACKGROUND: Although socioeconomic inequality in cardiovascular health has long been a public health focus, the differences in cardiovascular-disease burden and mortality between people with different socioeconomic statuses has yet to be adequately addressed. We aimed to assess the effects of socioeconomic status, measured via three socioeconomic-status indicators (ie, education, occupation, and household wealth and a composite socioeconomic-status disparity index, on mortality and cardiovascular-disease burden (ie, incidence, mortality, and admission to hospital) in China. METHODS: For this analysis, we used data from the Prospective Urban Rural Epidemiology (PURE)-China cohort study, which enrolled adults aged 35-70 years from 115 urban and rural areas in 12 provinces in China between Jan 1, 2005, and Dec 31, 2009. Final follow-up was on Aug 30, 2021. Indicators of socioeconomic status were education, occupation, and household wealth; these individual indicators were also used to create an integrated socioeconomic-status index via latent class analysis. Standard questionnaires administered by trained researchers were used to obtain baseline data and were supplemeted by physical measurements. The primary outcomes were all-cause mortality, cardiovascular-disease mortality, non-cardiovascular-disease mortality, major cardiovascular disease, and cardiovascular-disease admission to hospital. Hazard ratios (HRs) and average marginal effects were used to assess the association between the primary outcomes and socioeconomic status. FINDINGS: Of 47 931 participants enrolled in the PURE-China study, 47 278 (98·6%) had complete information on sex and follow-up. After excluding 1189 (2·5%) participants with missing data on education, household wealth, and occupation at baseline, 46 089 participants were included in this analysis. Median follow-up was 11·9 years (IQR 9·5-12·6); 26 860 (58·3%) of 46 089 participants were female and 19 229 (41·7%) were male. Having no or primary education, unskilled occupation, or being in the lowest third of household wealth was associated with a higher risk of all-cause mortality, cardiovascular-disease mortality, non-cardiovascular-disease mortality, major cardiovascular disease, and cardiovascular-disease admission to hospital compared with having higher education, a professional or managerial occupation, or more household wealth. After adjustment for confounders, people categorised as having low integrated socioeconomic status based on the index had a higher risk of all-cause mortality (HR 1·65 [95% CI 1·42-1·92]), cardiovascular-disease mortality (2·19 [1·68-2·85]), non-cardiovascular disease mortality (1·43 [1·18-1·72]), major cardiovascular disease (1·43 [1·27-1·61]) and cardiovascular-disease admission to hospital (1·14 [1·01-1·28]) compared with people categorised as having high integrated socioeconomic status. INTERPRETATION: Socioeconomic-status inequalities in mortality and cardiovascular-disease outcomes exist in China. Targeted policies of equal health-care resource allocation should be promoted to equitably benefit people with fewer years of education and less household wealth. FUNDING: Funding sources are listed at the end of the Article.

In vitro combination with doxycycline plus antifungals against clinical Mucorales pathogens.

PURPOSE: Since systematic antifungals for mucormycosis showed variable MICs depending on strains, effective and safe antifungal therapy was still needed. This study is aimed to evaluate the in vitro activity of doxycycline combined with antifungal therapy against dominant Mucorales pathogens. METHODS: Multidrug susceptibility testing was performed with doxycycline and antifungals, including itraconazole, posaconazole, and amphotericin, in 21 isolates of 8 dominant Mucorales pathogens. RESULTS: The fractional inhibitory concentration index according to M38 showed one Rhizopus arrhizus isolate synergic (∑FICI = 0.375) and other isolates in addition (0.5 < ∑FICI < 4). CONCLUSIONS: Doxycycline was found to have in vitro advantages in combined antifungal treatment over antifungals alone.