Vaccines against extraintestinal pathogenic Escherichia coli (ExPEC): progress and challenges.

The emergence of antimicrobial resistance (AMR) is a principal global health crisis projected to cause 10 million deaths annually worldwide by 2050. While the Gram-negative bacteria Escherichia coli is commonly found as a commensal microbe in the human gut, some strains are dangerously pathogenic, contributing to the highest AMR-associated mortality. Strains of E. coli that can translocate from the gastrointestinal tract to distal sites, called extraintestinal E. coli (ExPEC), are particularly problematic and predominantly afflict women, the elderly, and immunocompromised populations. Despite nearly 40 years of clinical trials, there is still no vaccine against ExPEC. One reason for this is the remarkable diversity in the ExPEC pangenome across pathotypes, clades, and strains, with hundreds of genes associated with pathogenesis including toxins, adhesins, and nutrient acquisition systems. Further, ExPEC is intimately associated with human mucosal surfaces and has evolved creative strategies to avoid the immune system. This review summarizes previous and ongoing preclinical and clinical ExPEC vaccine research efforts to help identify key gaps in knowledge and remaining challenges.

Cytokines and lymphocyte subsets are associated with disease severity of severe fever with thrombocytopenia syndrome.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by severe fever with thrombocytopenia syndrome virus (SFTSV). Previous studies have indicated that SFTS patients have a high mortality rate, which may be related to cytokine storm and immune dysfunction. In our study, we analyzed differences in cytokines and lymphocyte subsets between severe and non-severe SFTS patients, with the aim of identifying predictors of severity. METHODS: We retrospectively analyzed demographic characteristics, clinical data, cytokine profiles, and lymphocyte subsets from 96 laboratory confirmed SFTS patients between April 2021 and August 2023. RESULTS: A total of 96 SFTS patients were enrolled, with a mean age of 65.05 (± 7.92) years old. According to our grouping criteria, 35 (36.5%) of these patients were classified as severe group, while 61 (63.5%) were classified as non-severe group. Univariate analysis revealed that age, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interferon-α (IFN-α), CD4 + T cell, and CD8 + T cell counts were risk predictors for the severity of SFTS. Further multivariable logistic regression analysis confirmed age, IL-6 levels, and CD4 + T cell counts as independent predictors of SFTS severity. CONCLUSIONS: Severe SFTS patients may experience cytokine storms and immune dysfunction. Aging, elevated levels of IL-6, and decreased CD4 + T cell count may serve as independent predictors for the severity of SFTS.

Correction: Prevalence of High-Risk Human Papillomavirus Infection, Associated Risk Factors, and Relationship With Cervical Precancerous Lesions in Perimenopausal and Older Women in an Area With High Cervical Cancer Incidence in China.

[This corrects the article DOI: 10.7759/cureus.58081.].

Application value of metagenomic next-generation sequencing in hematological patients with high-risk febrile neutropenia.

Background: Metagenomic next-generation sequencing (mNGS) is a novel non-invasive and comprehensive technique for etiological diagnosis of infectious diseases. However, its practical significance has been seldom reported in the context of hematological patients with high-risk febrile neutropenia, a unique patient group characterized by neutropenia and compromised immune responses. Methods: This retrospective study evaluated the results of plasma cfDNA sequencing in 164 hematological patients with high-risk febrile neutropenia. We assessed the diagnostic efficacy and clinical impact of mNGS, comparing it with conventional microbiological tests. Results: mNGS identified 68 different pathogens in 111 patients, whereas conventional methods detected only 17 pathogen types in 36 patients. mNGS exhibited a significantly higher positive detection rate than conventional methods (67.7% vs. 22.0%, P < 0.001). This improvement was consistent across bacterial (30.5% vs. 9.1%), fungal (19.5% vs. 4.3%), and viral (37.2% vs. 9.1%) infections (P < 0.001 for all comparisons). The anti-infective treatment strategies were adjusted for 51.2% (84/164) of the patients based on the mNGS results. Conclusions: mNGS of plasma cfDNA offers substantial promise for the early detection of pathogens and the timely optimization of anti-infective therapies in hematological patients with high-risk febrile neutropenia.

Correction: Knowledge and Practices Regarding Human Papillomavirus and Cervical Cancer Screening Among Women in Low-Income Areas of China: A Cross-Sectional Study.

[This corrects the article DOI: 10.7759/cureus.55930.].

STAU1 exhibits a dual function by promoting amyloidogenesis and tau phosphorylation in cultured cells.

Staufen-1 (STAU1) is a double-stranded RNA-binding protein (RBP) involved in a variety of pathological conditions. In this study, we investigated the potential role of STAU1 in Alzheimer's disease (AD), in which two hallmarks are well-established as cerebral ß-amyloid protein (Aß) deposition and Tau-centered neurofibrillary tangles. We found that STAU1 protein level was significantly increased in cells that stably express full-length APP and the brain of APP/PS1 mice, an animal model of AD. STAU1 knockdown, as opposed to overexpression, significantly decreased the protein levels of ß-amyloid converting enzyme 1 (BACE1) and Aß. We further found that STAU1 extended the half-life of the BACE1 mRNA through binding to the 3' untranslated region (3'UTR). Transcriptome analysis revealed that STAU1 enhanced the expression of growth arrest and DNA damage 45 ß (GADD45B) upstream of P38 MAPK signaling, which contributed to STAU1-induced regulation of Tau phosphorylation at Ser396 and Thr181. Together, STAU1 promoted amyloidogenesis by inhibiting BACE1 mRNA decay, and augmented Tau phosphorylation through activating GADD45B in relation to P38 MAPK. Targeting STAU1 that acts on both amyloidogenesis and tauopathy may serve as an optimistic approach for AD treatment.

Integrated identification-quantification (ID-Quant) workflow utilizing UPLC-QTOF-MS for the therapeutic drug monitoring of multi-component antibiotics without pure standards: Validation using teicoplanin.

The lack of individual pure standard has hampered the application of therapeutic drug monitoring (TDM) for multi-component antibiotics in clinical laboratories. Here, we aimed to develop an integrated identification-quantification (ID-Quant) workflow based on ultra-high-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (UHPLC-QTOF-MS) to enable the comprehensive determination of all teicoplanin components without needing pure standards. The workflow comprises three steps. First, non-targeted MSE full scanning was used to detect and identify all potential ingredients. Then, characteristic product ions were selected to generate a quantitative time-of-flight multiple reaction monitoring (Tof-MRM) method. Finally, the constituent composition of teicoplanin injection was determined and utilized as an alternative reference standard to monitor the teicoplanin ingredients in human serum samples. As a result, nine teicoplanin analogs were identified from teicoplanin injection (Sanofi-Aventis, France). The overall performance of the Tof-MRM method was satisfactory in terms of linearity, precision, accuracy, and limits of detection. Utilizing the drug as standard, the individual concentrations for each component in patient serum were determined to be 0.120 µg/mL (A3-1), 0.020 µg/mL (N-1), 0.550 µg/mL (N-2), 0.730 µg/mL (A2-1), 4.26 µg/mL (A2-2,3), 4.79 µg/mL (A2-4,5), and 0.290 µg/mL (N-3), respectively. The distribution pattern of teicoplanin components was also discovered to differ from that in the drug injection. Overall, this integrated ID-Quant workflow based on UHPLC-QTOF-MS enables the robust quantitation of all teicoplanin analogs without the need for individual pure standard. This approach could help address the standard unavailability problem in the TDM of multi-component antibiotics.

Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice.

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

Thyroid stimulating receptor autoantibodies.

Thyroid-stimulating hormone receptor autoantibodies (TRAbs) play a crucial role as pathogenic antibodies in both the diagnosis and management of Graves' disease (GD). GD, an autoimmune disease resulting from a combination of genetic and environmental factors, is the most common cause of hyperthyroidism. With advancements in technology for TRAb detection and the availability of automated commercial kits, TRAb has become an essential clinical laboratory marker for the diagnosis of GD, as well as extra-thyroidal manifestations like Graves' ophthalmopathy (GO). This article provides a comprehensive review of TRAb, encompassing its clinical assays along with its significance in the clinical setting.

Association between Serum Lactate Dehydrogenase Level and 30-day Mortality in Patients with Intracranial Hemorrhage with Acute Leukemia in the Induction Phase: A Cohort Study.

Objectives This study aimed to identify the association between lactate dehydrogenase (LDH) levels and 30-day mortality in patients with intracranial hemorrhage (ICH) with acute leukemia during the induction phase. Methods This cohort study included patients with acute leukemia with ICH during induction. We evaluated serum LDH levels upon admission. Multivariable Cox regression analyzed the LDH 30-day mortality association. Interaction and stratified analyses based on factors like age, sex, albumin, white blood cell count, hemoglobin level, and platelet count were conducted. Results We selected 91 patients diagnosed with acute leukemia and ICH. The overall 30-day mortality rate was 61.5%, with 56 of the 91 patients succumbing. Among those with LDH levels ≥ 570 U/L, the mortality rate was 74.4% (32 out of 43), which was higher than the 50% mortality rate of the LDH < 570 U/L group (24 out of 48) ( p = 0.017). In our multivariate regression models, the hazard ratios and their corresponding 95% confidence intervals for Log2 and twice the upper limit of normal LDH were 1.27 (1.01, 1.58) and 2.2 (1.05, 4.58), respectively. Interaction analysis revealed no significant interactive effect on the relationship between LDH levels and 30-day mortality. Conclusions Serum LDH level was associated with 30-day mortality, especially in patients with LDH ≥ 570 U/L.

Reactive Oxygen Species Amplifier for Apoptosis-Ferroptosis Mediated High-Efficiency Radiosensitization of Tumors.

Insufficient reactive oxygen species (ROS) production and radioresistance have consistently contributed to the failure of radiotherapy (RT). The development of a biomaterial capable of activating ROS-induced apoptosis and ferroptosis is a potential strategy to enhance RT sensitivity. To achieve precision and high-efficiency RT, the theranostic nanoplatform Au/Cu nanodots (Au/CuNDs) were designed for dual-mode imaging, amplifying ROS generation, and inducing apoptosis-ferroptosis to sensitize RT. A large amount of ROS is derived from three aspects: (1) When exposed to ionizing radiation, Au/CuNDs effectively absorb photons and emit various electrons, which can interact with water to produce ROS. (2) Au/CuNDs act as a catalase-like to produce abundant ROS through Fenton reaction with hydrogen peroxide overexpressed of tumor cells. (3) Au/CuNDs deplete overexpressed glutathione, which causes the accumulation of ROS. Large amounts of ROS and ionizing radiation further lead to apoptosis by increasing DNA damage, and ferroptosis by enhancing lipid peroxidation, significantly improving the therapeutic efficiency of RT. Furthermore, Au/CuNDs serve as an excellent nanoprobe for high-resolution near-infrared fluorescence imaging and computed tomography of tumors. The promising dual-mode imaging performance shows their potential application in clinical cancer detection and imaging-guided precision RT, minimizing damage to adjacent normal tissues during RT. In summary, our developed theranostic nanoplatform integrates dual-mode imaging and sensitizes RT via ROS-activated apoptosis-ferroptosis, offering a promising prospect for clinical cancer diagnosis and treatment.

Prevalence of High-Risk Human Papillomavirus Infection, Associated Risk Factors, and Relationship With Cervical Precancerous Lesions in Perimenopausal and Older Women in an Area With High Cervical Cancer Incidence in China.

Purpose This study delves into the epidemiology of high-risk human papillomavirus (HR-HPV) infection and its link to precancerous lesions among perimenopausal (40-59 years) and elderly (60-65 years) women in a Chinese county with a notably high incidence of cervical cancer. By uniquely focusing on these age groups in underdeveloped regions, the research aims to offer novel strategies for the management and prevention of cervical cancer. It seeks to inform targeted interventions and public health policies that could significantly benefit women at heightened risk for HPV, addressing a critical gap in current prevention efforts in economically disadvantaged communities. Methods This observational study was conducted at the Maternal and Child Health and Family Planning Service Centre in Lueyang County, from September 2021 to January 2022. It assessed 2008 women aged 40-65 for HPV screening, with 342 undergoing further cytological examination. The study evaluated the prevalence of HPV infection across different age groups and risk categories. It utilized a questionnaire to collect participants' basic information, health behaviors, and other relevant data to analyze factors influencing HR-HPV infection. Statistical analyses comprised chi-square tests, trend analysis, logistic regression, and multiple imputation techniques to address missing data. Results The prevalence of HR-HPV infection among women aged 40-65 years in Lueyang County was 18.43%. Older women exhibited a higher incidence of HPV infection, abnormal ThinPrep Cytology Test (TCT) results (Shaanxi Fu'an Biotechnology Co. Ltd., Baoji City, China), and low/high-grade squamous intraepithelial lesions (LSIL/HSIL) (P<0.05). The most prevalent HR-HPV genotypes in the overall, perimenopausal, and elderly groups were HPV-52, -53, and -58; HPV-52, -53, and -16; and HPV-58, -52, and -53, respectively. The prevalent HR-HPV genotypes in the abnormal The Bethesda System (TBS) results were HPV-16, -52, -33, -58; -16, -52, -58; and-16, -33, and -52. HPV-16, -18, -33 prevalence increased with increasing lesion severity (P<0.05). In this study, factors affecting HR-HPV in the three age groups were found to be mainly related to sexual behavior and education level, including history of lower genital tract diseases, multiple pregnancies, contraceptive methods without tubal ligation, age at first marriage greater than 18 years, never washing the vulva after sex, abstinence from sex, education level of junior high school or above, and spouse's education level of high school or above. Conclusions These findings suggest that the elevated rate of abnormal TBS in the older age group may be attributed to the higher prevalence of persistent infection-prone HR-HPV genotypes (HPV-58, -52, and-53), multiple infections, and potent oncogenic HR-HPV genotypes (HPV-16 and -33). Additionally, the higher HR-HPV prevalence in older patients may be related to lower education attainment, reduced screening rate, and limited condom usage. Therefore, strategies targeting perimenopausal and older women should prioritize enhancing health awareness, increasing screening rates, and encouraging condom utilization.

A capillary-aided microfiber Bragg grating pH sensor for hydrovoltaic technology.

Hydrovoltaic is an emerging technology that aims to harvest energy from water flow and evaporation, in which the plasmonic hydrogen ions are generated by the interaction between water and hydrovoltaic device. However, the volume of the water sample for the interaction is usually ultra-small due to the compact size of hydrovoltaic device, making the quantification and characterization of the hydrogen ions in such water sample an elusive goal. To address this issue, a miniature fiber-optic pH probe is proposed using a unilaterally tapered-microfiber Bragg grating. The microfiber Bragg grating has an intrinsic Bragg reflection signal with a narrow linewidth. The fiber probe is functionalized by coating the sodium alginate, which can respond to the variation of pH mediated by the alteration of the hydrophilicity. The rigidity and robustness of microfiber Bragg grating facilitates the encapsulation of the sensor into a sampling capillary, allowing for the detection of trace aqueous sample less than 2 µL. The pH sensitivity of the tapered-µFBG-based sensor is 62.8 p.m./pH (R2 = 0.995) with a limit resolution of 0.096 pH. The sensor performed a practical application in the monitoring and characterization of the hydrovoltaic microdevice, which can generate microcurrent as soaked in the water. This work demonstrates a promising technology in the fields of materials, energy, biology and medicine, in which the detection of the microsamples is inevitable.

Preoperative exercise training decreases complications of minimally invasive lung cancer surgery: A randomized controlled trial.

OBJECTIVE: Limited evidence exists regarding the efficacy of preoperative exercise in reducing short-term complications after minimally invasive surgery in patients with non-small cell lung cancer. This study aims to investigate the impact of preoperative exercise on short-term complications after minimally invasive lung resection. METHODS: In this prospective, open-label, randomized (1:1) controlled trial at Xiangya Hospital, China (September 2020 to February 2022), patients were randomly assigned to a preoperative exercise group with 16-day alternate supervised exercise or a control group. The primary outcome assessed was short-term postoperative complications, with a follow-up period of 30 days postsurgery. RESULTS: A total of 124 patients were recruited (preoperative exercise group n = 62; control n = 62). Finally, 101 patients (preoperative exercise group; n = 51 and control; n = 50) with a median age of 56 years (interquartile range, 50-62 years) completed the study. Compared with the control group, the preoperative exercise group showed fewer postoperative complications (preoperative exercise 3/51 vs control 10/50; odds ratio, 0.17; 95% CI, 0.04-0.86; P = .03) and shorter hospital stays (mean difference, -2; 95% CI, -3 to -1; P = .01). Preoperative exercise significantly improved depression, stress, functional capacity, and quality of life (all P < .05) before surgery. Furthermore, preoperative exercise demonstrated a significantly lower minimum blood pressure during surgery and lower increases in body temperature on day 2 after surgery, neutrophil-to-lymphocyte ratio, and neutrophil count after surgery (all P < .05). Exploratory research on lung tissue RNA sequencing (5 in each group) showed downregulation of the tumor necrosis factor signaling pathway in the preoperative exercise group compared with the control group. CONCLUSIONS: Preoperative exercise training decreased short-term postoperative complications in patients with non-small cell lung cancer.

Knowledge and Practices Regarding Human Papillomavirus and Cervical Cancer Screening Among Women in Low-Income Areas of China: A Cross-Sectional Study.

BACKGROUND: Persistent human papillomavirus (HPV) infection is the primary cause of cervical cancer. However, this can be prevented through vaccination and screening. This study aimed to clarify the relationship between behavior, knowledge, and attitude toward cervical cancer and regular screening and HPV infection among women in Lueyang County. METHODS: Women who underwent cervical cancer screening at the outpatient department of a maternal and child health center between September and December 2021 were invited to participate. In total, 2,303 women completed the questionnaire. Women who underwent regular or irregular screening were 1:1 matched for age. Differences in knowledge of HPV and attitudes toward HPV vaccination among different populations were assessed. Logistic regression analysis was performed to identify the factors influencing HPV infection. RESULTS:  In total, 417 pairs of women who underwent regular and irregular screening were successfully matched. Multivariate logistic regression results indicated that age is a risk factor for HPV infection (OR=1.056 95%CI: [1.031 1.082]), while regular screening acts as a protective factor against HPV infection (OR=0.174 95%CI: [0.117 0.259]). Additionally, regular screening was associated with a higher level of knowledge about HPV among women compared to those who did not undergo regular screening (p<0.001). CONCLUSIONS:  Women in Lueyang County have low levels of knowledge regarding HPV and cervical cancer. Regular screening is a protective factor against HPV infection. The regular screening group demonstrates a higher level of HPV knowledge compared with the irregular screening group. These findings highlight the importance of regular screening and the need to strengthen public health education.

Legumain-Triggered Macrocyclization of Radiofluorinated Tracer for Enhanced PET Imaging.

Enhancing the accumulation and retention of small-molecule probes in tumors is an important way to achieve accurate cancer diagnosis and therapy. Enzyme-stimulated macrocyclization of small molecules possesses great potential for enhanced positron emission tomography (PET) imaging of tumors. Herein, we reported an 18F-labeled radiotracer [18F]AlF-RSM for legumain detection in vivo. The tracer was prepared by a one-step aluminum-fluoride-restrained complexing agent ([18F]AlF-RESCA) method with high radiochemical yield (RCY) (88.35 ± 3.93%) and radiochemical purity (RCP) (>95%). More notably, the tracer can be transformed into a hydrophobic macrocyclic molecule under the joint action of legumain and reductant. Simultaneously, the tracer could target legumain-positive tumors and enhance accumulation and retention in tumors, resulting in the amplification of PET imaging signals. The enhancement of radioactivity enables PET imaging of legumain activity with high specificity. We envision that, by combining this highly efficient 18F-labeled strategy with our intramolecular macrocyclization reaction, a range of radiofluorinated tracers can be designed for tumor PET imaging and early cancer diagnosis in the future.

Plasma Steroid Profiling Combined With Machine Learning for the Differential Diagnosis in Mild Autonomous Cortisol Secretion From Nonfunctioning Adenoma in Patients With Adrenal Incidentalomas.

OBJECTIVE: To assess the diagnostic value of combining plasma steroid profiling with machine learning (ML) in differentiating between mild autonomous cortisol secretion (MACS) and nonfunctioning adenoma (NFA) in patients with adrenal incidentalomas. METHODS: The plasma steroid profiles data in the laboratory information system were screened from January 2021 to December 2023. EXtreme Gradient Boosting was applied to establish diagnostic models using plasma 24-steroid panels and/or clinical characteristics of the subjects. The SHapley Additive exPlanation (SHAP) method was used for explaining the model. RESULTS: Seventy-six patients with MACS and 86 patients with NFA were included in the development and internal validation cohort while the external validation cohort consisted of 27 MACS and 21 NFA cases. Among 5 ML models evaluated, eXtreme Gradient Boosting demonstrated superior performance with an area under the curve of 0.77 using 24 steroid hormones. The SHAP method identified 5 steroids that exhibited optimal performance in distinguishing MACS from NFA, namely dehydroepiandrosterone, 11-deoxycortisol, 11ß-hydroxytestosterone, testosterone, and dehydroepiandrosteronesulfate. Upon incorporating clinical features into the model, the area under the curve increased to 0.88, with a sensitivity of 0.77 and specificity of 0.82. Furthermore, the results obtained through SHAP revealed that lower levels of testosterone, dehydroepiandrosterone, low-density lipoprotein cholesterol, body mass index, and adrenocorticotropic hormone along with higher level of 11-deoxycortisol significantly contributed to the identification of MACS in the model. CONCLUSIONS: We have elucidated the utilization of ML-based steroid profiling to discriminate between MACS and NFA in patients with adrenal incidentalomas. This approach holds promise for distinguishing these 2 entities through a single blood collection.

The oxytocin receptor is essential for the protective effect of pair housing on post-stroke depression in mice.

The beneficial effect of social interaction in mitigating the incidence of post-stroke depression (PSD) and ameliorating depressive symptoms has been consistently demonstrated through preclinical and clinical studies. However, the underlying relationship with oxytocin requires further investigation. In light of this, the present study aimed to explore the protective effect of pair housing on the development of PSD and the potential relationship with oxytocin receptors. The PSD model was induced by middle cerebral artery occlusion (MCAO) for 50 min, followed by 4-week isolated housing and restrained stress. Subsequently, each mouse in the pair-housing group (PH) was pair-housed with an isosexual healthy partner. Another group was continuously administrated fluoxetine (10 mg/Kg, i.p, once a day) for 3 weeks. To elucidate the potential role of oxytocin, we subjected pair-housed PSD mice to treatment with an oxytocin receptor (OXTR) antagonist (L368,889) (5 mg/Kg, i.p, once a day) for 3 weeks. At 31 to 32 days after MCAO, anxiety- and depressive-like behaviors were assessed using sucrose consumption, forced swim test, and tail-suspension test. The results showed that pair housing significantly improved post-stroke depression to an extent comparable to that of fluoxetine treatment. Furthermore, pair housing significantly decreased corticosterone in serum, increasing OXT mRNA expression in the hypothalamus. Treatment with L368,889 essentially reversed the effect of pair housing, with no discernible sex differences apart from changes in body weight. Pair housing increased hippocampal serotonin (5-HT), but treatment with L368,889 had no significant impact. Additionally, pair housing effectively reduced the number of reactive astrocytes and increased Nissl's body in the cortex and hippocampal CA3 regions. Correspondingly, treatment with L368,889 significantly reversed the changes in the Nissl's body and reactive astrocytes. Moreover, pair housing downregulated mRNA levels of TNF-α, IL-1ß, and IL-6 in the cortex caused by PSD, which was also reversed by treatment with L368,889. In conclusion, pair housing protects against the development of PSD depending on OXT and OXTR in the brain, with no significant divergence based on sex. These findings provide valuable insights into the potential of social interaction and oxytocin as therapeutic targets for PSD. Further research into the underlying mechanisms of these effects may contribute to the development of novel treatments for PSD.

Immunogenicity and safety of an ORF7-deficient skin-attenuated and neuro-attenuated live vaccine for varicella: a randomised, double-blind, controlled, phase 2a trial.

BACKGROUND: The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine). METHODS: We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log10 plaque forming units (PFU; low-dose v7D group), 3·9 log10 PFU (medium-dose v7D group), and 4·2 log10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434. FINDINGS: On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related. INTERPRETATION: The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.