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Pneumonia remains a leading cause of global mortality. Conventional diagnostic approaches frequently fail to distinguish microbial colonization from true infection in the lower respiratory tract, complicating clinical decision-making and contributing to antibiotic overuse. Improved diagnostic strategies are urgently needed. In this prospective, single-center study, deep sputum specimens were collected from patients with respiratory colonization (n = 17) and infectious pneumonia (n = 27) admitted to the neurosurgical ICU of Huashan Hospital. Metagenomic next-generation sequencing (mNGS) and metatranscriptomic profiling were performed to characterize both the pulmonary microbiota and the host immune response. These features were subsequently integrated to construct a diagnostic model. Microbial community profiling revealed reduced alpha diversity and enrichment of metabolically active pathogenic taxa in the infection group, consistent with a dysbiotic state permissive to invasion. In contrast, the colonization group demonstrated a more balanced microbial ecosystem. Transcriptomic analyses identified 2232 differentially expressed host genes between the two groups. The colonization group showed marked activation of the Wnt, MAPK, chemokine, and focal adhesion pathways, which are functionally implicated in epithelial barrier maintenance and early immune homeostasis. A multi-omics diagnostic model incorporating seven gene features (ANKRD52, ZC3HAV1L, SERPINE3, CDPF1, ZNF720, TAGLN3, and LRRC15) achieved a discrimination between colonization and infection (AUC = 0.951 in the training cohort; 0.875 in the validation set). By jointly analyzing the pulmonary microbiome and host transcriptome, this study provides insight into host–microbe interactions distinguishing colonization from infection and presents a predictive model with potential clinical relevance.

Background Extramammary Paget disease (EMPD) is a rare malignant dermatosis with poorly defined outcomes. We investigated clinical characteristics of invasive EMPD at different anatomic sites and by subject demographics to determine prognostic factors for overall survival (OS). Methods All patient data were collected from the Surveillance, Epidemiology, and End Results (SEER) program, 1973–2013, of the U.S. National Cancer Institute. Patients with invasive EMPD of skin, vulva/labia, vagina, scrotum/penis, or other sites were included. After excluding patients with unknown radiation status, data of 2001 patients were analyzed. Primary endpoint was EMPD mortality by anatomic sites. Independent variables included patients’ demographic data, concurrent malignancy (ie, non-EMPD related cancers), tumor size, distant metastasis, and surgery and/or radiation or not. Results Multivariate regression analysis showed that mortality was significantly higher in patients with vaginal EMPD than in patients with vulvar/labial EMPD (adjusted hazard ratio [aHR] = 3.26, p  < 0.001). Patients with distant metastasis had higher mortality than those without (aHR = 3.36, p  < 0.001). Patients who received surgery had significantly lower mortality than those who did not receive surgery (aHR = 0.77, p  = 0.030), and those treated with radiation had significantly higher mortality than those who did not receive radiation (aHR = 1.60, p  = 0.002). Older age was associated with significantly increased mortality (aHR = 1.09, p  < 0.001), and mortality was significantly higher in males than in females (aHR = 1.42, p  = 0.008). Conclusions In conclusion, among EMPD patients, mortality is higher in patients with vaginal EMPD than in those with vulvar/labial EMPD and higher in those who are older, those with concurrent malignancy or distant metastasis. Mortality is also higher in males than in females. Surgery is a protective factor and radiation is a risk factor for OS. Greater understanding of EMPD clinical characteristics, and considering EMPD in differential diagnosis of chronic genital and perianal dermatoses may provide support for early EMPD diagnosis and definitive surgical treatment.

Vesicovaginal fistula (VVF) is a devastating condition for female patients. We aimed to summarize our experience in the management of VVF and the surgical outcomes at our center and propose an algorithm for clinical practice. We conducted a retrospective study of patients with VVF who underwent surgical treatment at our center between January 2013 and December 2024. All patients were classified into non-irradiated and irradiated groups. Medical data were analyzed, including patient demographics, fistula characteristics, vaginal width, surgical procedures, surgical outcomes, and perioperative complications. We included 64 patients with VVF (20 non-irradiated and 44 irradiated). The fistula size in the irradiated group was mostly > 1.5 cm, whereas the size was <1.5 cm in the non-irradiated group. The vaginal width was > 3 cm in the fistula repair group, whereas it was < 3 cm in the urinary diversion group. For the non-irradiated group, we all performed fistula repair surgery, while only 47.7% in the irradiated group, where the remaining underwent urinary diversion (29.5%) or fistula repair + urinary diversion (22.7%). The irradiated group had a higher fistula recurrence rate than the non-irradiated group in both transvaginal (18.5% vs. 6.25%) and transabdominal (50% vs. 0%) approaches. We proposed an algorithm for the surgical management of VVFs based on radiation history, fistula size (>3 cm), and vaginal width (<3 cm). We suggest that transvaginal approach is the first option for fistula repair. For irradiated VVFs, transvaginal fistula repair with tissue interposition combined with permanent cystostomy demonstrated high success in our series, which is a valuable method.

Background Nuclear receptor subfamily 5 group A member 1 ( NR5A1 ) plays pivotal roles in steroidogenesis and gonadal development. 46, XY disorder of sexual development (DSD) caused by NR5A1 mutations is a rare genetic condition. This study aimed to provide a comprehensive analysis of the clinical characteristics and molecular defects observed in 19 Chinese patients with NR5A1 variants, including assessing the deleterious effects of novel variants in vitro and evaluating their functional impact on the gonad and adrenal glands in vivo. Materials and methods Subjects with NR5A1 variants were identified from 223 Chinese 46, XY DSD patients via next-generation sequencing. In-silico analysis and functional assays were performed to evaluate the transcriptional activity, expression levels and nuclear localization of novel NR5A1 variants. The histological structure of the gonads was evaluated via immunohistochemistry (IHC). Results Patients with NR5A1 gene variants presented with serious conditions, including micropenis, cryptorchidism, azoospermia, and radiological abnormalities of the spleen. Five novel NR5A1 variants were identified, including heterozygous p.Y5*, p.Q42E and p.L359_L363del, as well as copy number variation (CNV) of chr9:127213317–127570245_del and an exon 6 duplication. A total of 63.2% (12/19) of patients harbored additional variants other than NR5A1 . Defective transcriptional regulatory activities and abnormal protein expression levels were observed in NR5A1 variants. The reduced levels of DHEA-S and 11-oxygenated steroids indicate a mild impairment in adrenal function among certain patients. The IHC analysis of the testis revealed intact expression levels of SOX9 in Sertoli cells, while significant differences were observed in the expression pattern of CYP17A1 in Leydig cells among patients. The preserved maturation of adult Leydig cells in the patients may trigger spontaneous puberty. Conclusions Patients with NR5A1 mutations exhibit complex phenotypes. The observed clinical heterogeneity may be attributed to oligogenic mutations, dysregulated Leydig cell function, as well as the impaired ability to modulate the transcription of target genes.

The current study sought to clarify the role of lysozyme-regulated gut microbiota and explored the potential therapeutic effects of lysozyme on ileum injury induced by severe traumatic brain injury (sTBI) and bacterial pneumonia and experiments. Male 6-8-week-old specific pathogen-free (SPF) C57BL/6 mice were randomly divided into Normal group (N), Sham group (S), sTBI group (T), sTBI + or Lysozyme-treated group (L), Normal + Lysozyme group (NL) and Sham group + Lysozyme group (SL). At the day 7 after establishment of the model, mice were anesthetized and the samples were collected. The microbiota in lungs and fresh contents of the ileocecum were analyzed. Lungs and distal ileum were used to detect the degree of injury. The number of Paneth cells and the expression level of lysozyme were assessed. The bacterial translocation was determined. Intestinal organoids culture and co-coculture system was used to test whether lysozyme remodels the intestinal barrier through the gut microbiota. After oral administration of lysozyme, the intestinal microbiota is rebalanced, the composition of lung microbiota is restored, and translocation of intestinal bacteria is mitigated. Lysozyme administration reinstates lysozyme expression in Paneth cells, thereby reducing intestinal permeability, pathological score, apoptosis rate, and inflammation levels. The gut microbiota, including , , , , and , play a crucial role in regulating and improving intestinal barrier damage and modulating Paneth cells in lysozyme-treated mice. A co-culture system comprising intestinal organoids and brain-derived proteins (BP), which demonstrated that the BP effectively downregulated the expression of lysozyme in intestinal organoids. However, supplementation of lysozyme to this co-culture system failed to restore its expression in intestinal organoids. The present study unveiled a virtuous cycle whereby oral administration of lysozyme restores Paneth cell's function, mitigates intestinal injury and bacterial translocation through the remodeling of gut microbiota.

Background Androgen insensitive syndrome (AIS) is a rare genetic disease resulting from androgen receptor ( AR ) mutations and one of the causes of 46, XY disorder of sexual development (DSD). This study aimed to describe the clinical features and molecular defects of 36 Chinese patients with AR variants and investigate the functional alterations of novel variants in vitro. Material and methods Subjects with AR variants were identified from 150 Chinese 46, XY DSD patients using targeted next-generation sequencing. In-silico and functional assays were performed to evaluate the transcriptional activity and nuclear localization of novel AR variants. Results Eight novel and fifteen reported AR variants were identified. 30.6% (11/36) of patients harbored additional variants other than AR . Mutations in the Arg841 residue were found in 7 unrelated patients. Postpubertal serum gonadotropin levels were significantly elevated in patients with complete AIS (CAIS) compared with those in patients with partial AIS (PAIS) ( P  < 0.05). All the novel variants initially predicted to be uncertain significance by in-silico analyses were reclassified as likely pathogenic for defective AR transcriptional activity in vitro, except p.L295P, which was found in an atypical patient with oligogenic mutations and reclassified as likely benign. c.368_369 ins T was observed to interfere with nuclear translocation. Conclusions Compared with PAIS patients, postpubertal CAIS patients had higher gonadotropin levels. Arg841 was disclosed as the location of recurrent mutations in Chinese AIS patients. Functional assays are important for reclassifying the novel AR variants and re-examining the diagnosis of AIS in specific patients with oligogenic mutations, instead of in-silico analysis.

Objective: How to choose the appropriate antibiotics and dosage has always been a difficult issue during the treatment of multi-drug-resistant bacterial infections. Our study aims to resolve this difficulty by introducing our multi-disciplinary treatment (MDT) clinical decision-making scheme based on rigorous interpretation of antibiotic susceptibility tests and precise therapeutic drug monitoring (TDM)-guided dosage adjustment. Method: The treatment course of an elderly patient who developed a multi-drug-resistant Pseudomonas aeruginosa (MDRPA) bloodstream infection from a brain abscess was presented. Results: In the treatment process, ceftazidime–avibactam (CAZ–AVI) was used empirically for treating the infection and clinical symptoms improved. However, the follow-up bacterial susceptibility test showed that the bacteria were resistant to CAZ–AVI. Considering the low fault tolerance of clinical therapy, the treatment was switched to a 1 mg/kg maintenance dose of susceptible polymyxin B, and TDM showed that the AUC 24h, ss of 65.5 mgh/L had been achieved. However, clinical symptoms were not improved after 6 days of treatment. Facing the complicated situation, the cooperation of physicians, clinical pharmacologists, and microbiologists was applied, and the treatment finally succeeded with the pathogen eradicated when polymyxin B dose was increased to 1.4 mg/kg, with the AUC 24h, ss of 98.6 mgh/L. Conclusion: MDT collaboration on the premise of scientific and standardized drug management is helpful for the recovery process in patients. The empirical judgment of doctors, the medication recommendations from experts in the field of TDM and pharmacokinetics/pharmacodynamics, and the drug susceptibility results provided by the clinical microbiology laboratory all provide the direction of treatment.

Steroid 5α‐reductase type 2 deficiency (5α‐RD2) and androgen insensitivity syndrome (AIS) are difficult to distinguish clinically and biochemically, and adrenal‐derived androgens have not been investigated in these conditions using modern methods. The objective of the study was to compare Chinese patients with 5α‐RD2, AIS, and healthy men. Sixteen patients with 5α‐RD2, 10 patients with AIS, and 39 healthy men were included. Serum androgen profiles were compared in these subjects using liquid chromatography/tandem mass spectrometry (LC‐MS/MS). Based on clinical features and laboratory tests, 5α‐RD2 and AIS were diagnosed and confirmed by genotyping. Dihydrotestosterone (DHT) and testosterone (T) were both significantly lower in patients with 5α‐RD2 than AIS (p < 0.0001). The T/DHT ratio was higher in 5α‐RD2 (4.5–88.6) than AIS (13.4–26.7) or healthy men (7.6–40.5). Using LC‐MS/MS, a cutoff T/DHT value of 27.3 correctly diagnosed 5α‐RD2 versus AIS with sensitivity 93.8% and specificity 100%. Among the adrenal‐derived 11‐oxygenated androgens, 11β‐hydroxyandrostenedione (11OHA4) and 11‐ketoandrostenedione (11KA4) were also lower in patients with 5α‐RD2 than those of patients with AIS. In contrast, 11β‐hydroxytestosterone (11OHT) was higher in 5α‐RD2 than AIS. Furthermore, a 11OHT/11OHA4 cutoff value of 0.048 could also distinguish 5α‐RD2 from AIS. Thus, both elevated T/DHT values above 27.3 and the unexpected 11‐oxygenated androgen profile, with a 11OHT/11OHA4 ratio greater than 0.048, distinguished 5α‐RD2 from AIS. These data suggest that the metabolism of both gonadal and adrenal‐derived androgens is altered in 5α‐RD2.

Patients with brain injuries are at a heightened susceptibility to bacterial pneumonia, and the timely initiation of empiric antibiotic treatment has been shown to substantially reduce mortality rates. Nevertheless, there is a need for knowledge regarding the resistance and prevalence of pulmonary bacterial infections in this patient population. To address this gap, a retrospective study was conducted at a neurosurgical emergency center, focusing on patients with brain injuries. Among the entire patient population, a total of 739 individuals (18.23%) were identified as having bacterial pneumonia, consisting of 1489 strains of Gram-negative bacteria and 205 strains of Gram-positive bacteria. The resistance of Klebsiella pneumoniae to imipenem exhibited a significant increase, rising from 21.74% in 2009 to 96.67% in 2018, and subsequently reaching 48.47% in 2021. Acinetobacter baumannii displayed resistance rates exceeding 80.0% against multiple antibiotics. The resistance profile of Pseudomonas aeruginosa was relatively low. The proportion of Staphylococcus aureus reached its peak at 18.70% in 2016, but experienced a decline to 7.83% in 2021. The abundance of Gram-negative bacteria exceeded that of Gram-positive bacteria by a factor of 5.96. Klebsiella pneumoniae, Acinetobacter baumannii, and Staphylococcus aureus are prominent pathogens characterized by limited antibiotic choices and scarce treatment alternatives for the isolated strains.

Purpose: Carbapenem-resistant organisms (CROs) have posed a great threat to antibiotic use and induce multi-drug resistance. Contamination of the hospital environment and infection of healthcare workers (HCWs) are reported as sources of nosocomial infections. Here, we performed a comprehensive environment sampling and timely epidemiological investigation during outbreaks to investigate the role of the environment and HCWs in CRO transmission. Patients and Methods: We enrolled carbapenem-resistant organism outbreaks in ICU-1 of Huashan Hospital from January 2019 to March 2019, and ICU-2 located at west branch of Huashan Hospital from October 2019 to November 2019. Carbapenem- resistant Klebsiella pneumoniae (CRKP) and carbapenem-resistant Acinetobacter baumannii (CRAB) isolates were collected from the patients. We performed a real-time comprehensive environmental and HCW sampling in the two ICUs. Isolated strains from patients and the positive colonies from the screening were sent for whole-genome sequencing. Finally, phylogenetic trees were constructed. Results: CRAB and CRKP outbreaks simultaneously occurred in ICU-1; the outbreak involved 13 patients. Meanwhile, the CRKP outbreak in ICU-2 included 11 patients. Twelve out of 146 environment and HCWs samples in ICU-1 were carbapenem- resistant bacteria, including six CRKP and six CRAB strains. For ICU-2, hospital surfaces and HCWs were negative for CRKP. Phylogenetic analyses showed that CRKP strains in ICU-1 were classified into two clades: Clade 1 and Clade 2, sharing a high similarity of isolates from the environment and HCWs. The same phenomenon was observed in CRAB. Conclusion: A timely comprehensive sampling combined with genome-based investigation may aid in tracking the transmission route of and controlling the infections. The environment and HCWs could be contaminated during CRO transmission, which calls for strengthened prevention and control measures. Keywords: carbapenem-resistant, environment, whole-genome sequencing, prevention, control