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Bernice Tsoi,1,2 Gord Blackhouse,1,2 Simon Ferrazzi,3 Clare J Reade,4 Innie Chen,5,6 Ron Goeree1,2,7 1Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada; 2Programs for Assessment of Technology in Health (PATH) Research Institute, St Joseph's Healthcare Hamilton, Hamilton, ON, Canada; 3Independent Consultant, Oakville, ON, Canada; 4Division of Gynecologic Oncology, University of Toronto, Toronto, ON, Canada; 5Department of Obstetrics and Gynaecology, University of Ottawa, 6Ottawa Hospital Research Institute, Ottawa, ON, Canada; 7Centre for Evaluation of Medicines (CEM), St Joseph's Healthcare Hamilton, Hamilton, ON, Canada Objective: To present a Canadian economic evaluation on the cost-utility of ulipristal acetate (5 mg orally daily) compared to leuprolide acetate (3.75 mg intramuscular monthly) in the treatment of moderate-to-severe symptoms of uterine fibroids in women eligible for surgery. Methods: A probabilistic decision tree was constructed to model the pre-operative pharmacological management of uterine fibroids under the primary perspective of the Ontario public payer. The model parameterized data from clinical trials, observational studies, and public costing databases. The outcome measure was the incremental cost-utility ratio. Uncertainty in the model was explored through sensitivity and scenario analyses. Results: Ulipristal was associated with faster control of excessive menstrual bleeding, fewer symptoms of hot flashes and lower health care resource consumption. The ulipristal strategy dominated leuprolide as it provided patients with more quality-adjusted life years (0.177 versus 0.165) at a lower cost ($1,273 versus $1,366). Across a range of sensitivity analyses, the results remained robust except to the dose of the comparator drug. If leuprolide was administered at 11.25 mg, once every 3 months, the expected cost for the leuprolide strategy would decline and the associated incremental cost-utility ratio for ulipristal would be $168/quality-adjusted life year. Conclusion: Ulipristal offers a unique opportunity to effectively and rapidly control menstrual bleeding in patients with uterine fibroids; thereby improving their quality of life while minimizing the probability of moderate-to-severe hot flashes that are common with leuprolide. The current economic analysis suggests that ulipristal remains the dominant strategy across extensive sensitivity analyses. Keywords: cost-utility analysis, uterine leiomyomas, preoperative care, decision tree, menorrhagia

Fruits of Fructus Schisandrae were used as sedatives and hypnotics in traditional Chinese medicine for a long history. In this study, we investigated the effects of schisandra lignans extract (SLE) on anxiety disorder in restraint-stressed mice using light-dark (L-D) test. The influences of restraint stress on the levels of monoamines: noradrenaline (NE), dopamine (DA) and serotonin (5-HT) in cerebral cortex, as well as plasma corticosterone (CORT) were studied in mice. The HPLC fingerprint of SLE was recorded and the percentage composition of Schisandra lignans was determined as 82.63%. In L-D test, it was found out that 18h of restraint stress significantly decreased the anxiolytic parameters (explorative behaviors, e.g. number of entries, time spent) in light area indicating high state of anxiety in stressed mice. In addition, restraint stress elevated NE, DA, and 5-HT levels in cerebral cortex of anxiety mice. Plasma CORT level was also increased. Oral administration of SLE (100 and 200mg/kg/day, 8 days) emolliating the level of stress-induced anxiety by significantly increasing the anxiolytic parameters mentioned above. We also observed decreases in cerebral cortex monoamines levels, as well as plasma CORT level in stressed mice. These results suggested that SLE reversed stress-induced anxiety level, changes of cortex monoamine transmitters and plasma CORT. The anxiolytic effects of SLE might be related to its anti-stress activity by modulation of hyperactive HPA axis. [ABSTRACT FROM AUTHOR]

Abstract Background Lutein is an important eye-protective nutrient. This study investigates the protective effects and mechanisms of lutein on lipopolysaccharides (LPS)-induced uveitis in mice. Methods Lutein, suspended in drinking water at a final concentration of 12.5 and 25 mg/mL, was administered to mice at 0.1 mL/10 g body weight for five consecutive days. Control and model group received drinking water only. Uveitis was induced by injecting LPS (100 mg per mouse) into the footpad in the model and lutein groups on day 5 after the last drug administration. Eyes of the mice were collected 24 hours after the LPS injection for the detection of indicators using commercial kits and reverse transcription-polymerase chain reaction. Results LPS-induced uveitis was confirmed by significant pathological damage and increased the nitric oxide level in eye tissue of BALB/C mice 24 hours after the footpad injection. The elevated nitric oxide level was significantly reduced by oral administration of lutein (125 and 500 mg/kg/d for five days) before LPS injection. Moreover, lutein decreased the malondialdehyde content, increased the oxygen radical absorbance capacity level, glutathione, the vitamin C contents and total superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Lutein further increased expressions of copper-zinc SOD, manganese SOD and GPx mRNA. Conclusion The antioxidant properties of lutein contribute to the protection against LPS-induced uveitis, partially through the intervention of inflammation process.

Background: Sclerostin (SOST) is traditionally regarded as an osteocyte-derived secreted glycoprotein that regulates bone mineralization. Recent studies reported that SOST is also released from non-skeletal sources, especially during inflammation. However, the cellular source and regulatory mechanisms governing SOST generation in inflammation remain unclear. This study investigated whether macrophages produce SOST in response to inflammatory stimuli and determined associated regulatory pathways., Methods: The effect of lipopolysaccharide (LPS)-induced inflammation in SOST generation and its underlying regulatory mechanism was examined on mouse macrophage RAW 264.7 by western blot and immunofluorescent staining. Transfection with miR-92a-3p mimic and inhibitor were used to validate its role in SOST production. The role of NF-κB and TLR4 were studied using pharmacological inhibitors BAY 11-7085 and TAK242, respectively. The involvement of NF-κB and TLR4 in LPS-induced SOST production was further validated through nuclear NF-κB p65 immunoprecipitation and TLR4 small interfering RNA (siRNA) experiments, respectively.GW4869 and manumycin A (extracellular vesicles (EV) biogenesis inhibitors) were used to examine the associated of SOST and EV. Finally, SOST expression and characteristics of the isolated EV were assessed by Western blot and nanoparticle tracking analysis (NTA)., Results: LPS significantly induced SOST protein expression and secretion in RAW 264.7. MiR-92a-3p was upregulated by LPS stimulation in macrophages. Transfection of miR-92a-3p mimic increased SOST generation in RAW 264.7. Inhibition of TLR4 and NF-κB signalling pathways using pharmacological inhibitors significantly suppressed LPS-induced SOST in RAW 264.7. Similarly, TLR4 siRNA effectively suppressed LPS-induced SOST level. However, the LPS-induced upregulation of miR-92a-3p was only regulated by TLR4, but not by NF-κB. NF-κB was found to directly bind to the mouse sost promoter, thereby activating sost transcription. Additionally, SOST secretion was found predominantly associated with EV from LPS-stimulated cells, and inhibition of EV biogenesis suppressed SOST production in RAW 264.7 cells., Conclusions: In conclusion, our study showed, for the first time, that LPS induced SOST generation and secretion via TLR4/miR-92a-3p/PTEN/NF-κB singling pathway in murine macrophage RAW 264.7 cells. Moreover, we showed that SOST is secreted from the RAW 264.7 cells in the form of extracellular vesicle. This study identified macrophage as a novel source of SOST, highlighting its potential role in inflammatory diseases., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Alcoholic beverages are among the most widely enjoyed leisure drinks around the world. However, irresponsible drinking habits can have detrimental effects on human health. Therefore, exploring strategies to alleviate discomfort following alcohol consumption would be beneficial for individuals who inevitably need to consume alcohol. In this study, three different models were used to determine the efficacy of a patented alcohol degradation protein (ADP) extracted from Bos taurus on ethanol metabolism. In an ethanol-challenged HepG2 cell model, ADP significantly protected the cell from ethanol-induced toxicity. Subsequently, results demonstrated that ADP significantly alleviated the effect of ethanol, as reflected by the increased distance and activity time of zebrafish during the testing period. Additionally, in a rat model, ADP promoted ethanol degradation at 1 and 2 h after ethanol consumption. Mechanistic studies found that ADP treatment increased ADH and ALDH activity in the gastrointestinal tract. ADP also exhibited potent antioxidation effects by lowering HO-1 expression in the liver. In conclusion, we believe that ADP is a promising product for relieving hangover symptoms after ethanol consumption, with demonstrated safety and effectiveness at the recommended dosage.

Introduction: Chronic stress-associated hormonal imbalance impairs hippocampal neurogenesis, contributing to depressive and anxiety behaviors. Targeting neurogenesis is thus a promising antidepressant therapeutic strategy. Niuhuang Qingxin Wan (NHQXW) is an herbal formula for mental disorders in Traditional Chinese Medicine (TCM) practice, but its anti-depressant efficacies and mechanisms remain unverified. Methods: In the present study, we tested the hypothesis that NHQXW could ameliorate depressive-like behaviors and improve hippocampal neurogenesis by modulating the TrkB/ERK/CREB signaling pathway by utilizing two depression mouse models including a chronic restraint stress (CRS) mouse model and a chronic corticosterone (CORT) stress (CCS) induced mouse model. The depression-like mouse models were orally treated with NHQXW whereas fluoxetine was used as the positive control group. We evaluated the effects of NHQXW on depressive- and anxiety-like behaviors and determined the effects of NHQXW on inducing hippocampal neurogenesis. Results: NHQXW treatment significantly ameliorated depressive-like behaviors in those chronic stress mouse models. NHQXW significantly improved hippocampal neurogenesis in the CRS mice and CCS mice. The potential neurogenic mechanism of NHQXW was identified by regulating the expression levels of BDNF, TrkB, p-ERK (T202/T204), p-MEK1/2 (S217/221), and p-CREB (S133) in the hippocampus area of the CCS mice. NHQXW revealed its antidepressant and neurogenic effects that were similar to fluoxetine. Moreover, NHQXW treatment revealed long-term effects on preventing withdrawal-associated rebound symptoms in the CCS mice. Furthermore, in a bioactivity-guided quality control study, liquiritin was identified as one of the bioactive compounds of NHQXW with the bioactivities of neurogenesis-promoting effects. Discussion: Taken together, NHQXW could be a promising TCM formula to attenuate depressive- and anxiety-like behaviors against chronic stress and depression. The underlying anti-depressant mechanisms could be correlated with its neurogenic activities by stimulating the TrkB/ERK/CREB signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Du, Gao, Tsoi, Wu and Shen.)

Introduction: Hispanic/Latino men who have sex with men (MSM) and transgender women (TGW) are disproportionately affected by HIV in the U.S. This study evaluated HIV prevention services and outcomes among Hispanic/Latino MSM and TGW in the Targeted Highly Effective Interventions to Reduce the HIV Epidemic (THRIVE) demonstration project and consider lessons learned., Methods: The authors described the THRIVE demonstration project services provided to Hispanic/Latino MSM and TGW in 7 U.S. jurisdictions from 2015 to 2020. HIV prevention service outcomes were compared between 1 site with (2,147 total participants) and 6 sites without (1,129 total participants) Hispanic/Latino-oriented pre-exposure prophylaxis clinical services, and Poisson regression was used to estimate the adjusted RR between sites and pre-exposure prophylaxis outcomes. Analyses were conducted from 2021 to 2022., Results: The THRIVE demonstration project served 2,898 and 378 Hispanic/Latino MSM and TGW, respectively, with 2,519 MSM (87%) and 320 TGW (85%) receiving ≥1 HIV screening test. Among 2,002 MSM and 178 TGW eligible for pre-exposure prophylaxis, 1,011 (50%) MSM and 98 (55%) TGW received pre-exposure prophylaxis prescriptions, respectively. MSM and TGW were each 2.0 times more likely to be linked to pre-exposure prophylaxis (95% CI=1.4, 2.9 and 95% CI=1.2, 3.6, respectively) and 1.6 and 2.1 times more likely to be prescribed pre-exposure prophylaxis (95% CI=1.1, 2.2 and 95% CI=1.1, 4.1), respectively, at the site providing Hispanic/Latino-oriented pre-exposure prophylaxis clinical services than at other sites and adjusted for age group., Conclusions: The THRIVE demonstration project delivered comprehensive HIV prevention services to Hispanic/Latino MSM and TGW. Hispanic/Latino-oriented clinical settings may improve HIV prevention service delivery to persons in Hispanic/Latino communities., (Published by Elsevier Inc.)

Objectives: Neuroinflammation has been suggested that affects the processing of depression. There is renewed interest in berberine owing to its anti-inflammatory effects. Herein, we investigated whether berberine attenuate depressive-like behaviors via inhibiting NLRP3 inflammasome activation in mice model of depression., Methods: Adult male C57BL/6N mice were administrated corticosterone (CORT, 20 mg/kg/day) for 35 days. Two doses (100 mg/kg/day and 200 mg/kg/day) of berberine were orally administrated from day 7 until day 35. Behavioral tests were performed to measure the depression-like behaviors alterations. Differentially expressed gene analysis was performed for RNA-sequencing data in the prefrontal cortex. NLRP3 inflammasome was measured by quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence labeling. The neuroplasticity and synaptic function were measured by immunofluorescence labeling, Golgi-Cox staining, transmission electron microscope, and whole-cell patch-clamp recordings., Results: The results of behavioral tests demonstrated that berberine attenuated the depression-like behaviors induced by CORT. RNA-sequencing identified that NLRP3 was markedly upregulated after long-term CORT exposure. Berberine reversed the concentrations of peripheral and brain cytokines, NLRP3 inflammasome elicited by CORT in the prefrontal cortex and hippocampus were decreased by berberine. In addition, the lower frequency of neuronal excitation as well as the dendritic spine reduction were reversed by berberine treatment. Together, berberine increases hippocampal adult neurogenesis and synaptic plasticity induced by CORT., Conclusion: The anti-depressants effects of berberine were accompanied by reduced the neuroinflammatory response via inhibiting the activation of NLRP3 inflammasome and rescued the neuronal deterioration via suppression of impairments in synaptic plasticity and neurogenesis., (© 2023. The Author(s).)

Background: On 30 January 2020, COVID-19 was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization. Almost a month later, on 29 February 2020, the first case in New York City (NYC) was diagnosed., Methods: Three hundred sixty persons with COVID-19-like illness were reported to the NYC Department of Health and Mental Hygiene (DOHMH) before 29 February, but 37 of these tested negative and 237 were never tested for severe acute respiratory syndrome coronavirus 2. Records of 86 persons with confirmed COVID-19 and reported symptom onset prior to 29 February 2020 were reviewed by 4 physician-epidemiologists. Case-patients were classified as possible delayed recognition (PDR) of COVID-19 when upon medical review the reported onset date was believed to reflect the initial symptoms of COVID-19, or insufficient evidence to classify, when the onset could not be determined with confidence. Clinical and epidemiological factors collected by DOHMH and supplemented with emergency department records were analyzed., Results: Thirty-nine PDR COVID-19 cases were identified. The majority had severe disease with 69% presenting to an emergency department within 2 weeks of symptom onset. The first PDR COVID-19 case had symptom onset on 28 January 2020. Only 7 of the 39 cases (18%) had traveled internationally within 14 days of onset (none to China)., Conclusions: COVID-19 was in NYC before being classified as a PHEIC, and eluded surveillance for another month. The delay in recognition limited mitigation efforts; by the time city- and statewide mandates were enacted, 16 and 22 days later, there was already widespread community transmission., Competing Interests: Potential conflicts of interest. B. T. reports grants or contracts from the CDC, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In-depth qualitative interviews explored the experiences and understandings of men 18-39 years old who have sex with men that could facilitate or prevent HIV testing and routine HIV testing. For many men who tested frequently, testing and routine testing were motivated by awareness of the benefit of prompt treatment; public health and provider encouragement to test periodically; responsibility towards sexual partners; and wanting to share a recent HIV-negative test result when seeking sex online. For some men, any testing was impeded by anxiety around possible HIV diagnosis that made testing a stressful occasion that required time and energy to prepare for. This anxiety was often compounded by stigma related to sex between men, having condomless sex, or having HIV. Routine testing could be further stigmatized as some men felt judged by testing providers or partners if they asked for a test or said they tested frequently. We describe efforts to promote testing and routine testing by countering fear and stigma associated with HIV and testing., (© 2022. The Author(s).)

Background: Uptake of pre-exposure prophylaxis (PrEP) in the US has been limited. Evidence for why and how PrEP has been successfully integrated into some clinical settings, but not in others is minimal. To address this gap, we conducted a qualitative study to identify contextual factors that facilitated and challenged the implementation of PrEP services., Setting: In partnership with the NYC Department of Health, we convened a planning committee with expertise with groups highly affected by the HIV epidemic employed in diverse health care settings, to guide the project. Representatives from programs within New York were targeted for participation initially and subsequently expanded nationally to enhance diversity in program type., Methods: Using an interview guide informed by the Consolidated Framework for Implementation Research, we conducted 20 interviews with participants who successfully implemented PrEP programs in different settings (eg, primary care, emergency department, sexual health clinics), using different delivery models. We used template and matrix analysis to identify and characterize contextual determinants and implementation strategies., Results: Participants frequently described determinants and strategies fluidly and conceptualized them in context-specific terms. Commonly discussed Consolidated Framework for Implementation Research constructs included implementation climate (tension for change, compatibility, relatively priority), stakeholders' knowledge (or lack thereof) and beliefs about PrEP, and costs associated with PrEP implementation., Conclusion: Our work identifies patterns in PrEP program implementation, describing how organizations dealt with determinants in their own context. Our research points to the need to connect rigorous implementation research with how frontline implementers conceptualize their work to inform and improve PrEP implementation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hemorrhagic transformation (HT) is a common complication of delayed tissue plasminogen activator (t-PA) treatment for ischemic stroke. Peroxynitrite plays an important role in the breakdown of blood-brain barrier (BBB) and the development of HT. We tested the hypothesis that Angong Niuhuang Wan (AGNHW), a traditional Chinese medicinal formula, could be used in conjunction with t-PA to protect the BBB, minimize HT, and improve neurological function by suppressing peroxynitrite-mediated matrix metalloproteinase-9 (MMP-9) activation., Methods: We first performed quality control study and chemical identification of AGNHW by using UPLC. In animal experiments, male Sprague-Dawley rats were subjected to 5 h of middle cerebral artery occlusion (MCAO) followed by 19 h of reperfusion plus t-PA infusion (10 mg/kg) at 5 h of cerebral ischemia. AGNHW (257 mg/kg) was given orally at 2 h after MCAO. Hemorrhagic transformation was measured using hemorrhagic scores and hemoglobin levels in ischemic brains. Evans blue leakage was utilized to assess the severity of the blood-brain barrier (BBB) damage. The modified neurologic severity score (mNSS) test was used to assess neurological functions. Peroxynitrite and superoxide was detected by using fluorescent probes. MMP-9 activity and expression were examined by gelatin zymography and immunostaining. The antioxidant effects were also studied by using brain microvascular endothelial b.End3 cells exposed to 5 h of oxygen and glucose deprivation (OGD) plus 5 h of reoxygenation with t-PA treatment (20 µg/ml)., Results: AGNHW significantly reduced the BBB damage, brain edema, reduced hemorrhagic transformation, enhanced neurological function, and reduced mortality rate in the ischemic stroke rats with t-PA treatment. AGNHW reduced peroxynitrite and superoxide in vivo and in vitro and six active chemical compounds were identified from AGNHW with peroxynitrite scavenging activity. Furthermore, AGNHW inhibited MMP-9 activity, and preserved tight junction protein claudin-5 and collagen IV in the ischemic brains., Conclusion: AGNHW could be a potential adjuvant therapy with t-PA to protect the BBB integrity, reduce HT, and improve therapeutic outcome in ischemic stroke treatment via inhibiting peroxynitrite-mediated MMP-9 activation., (© 2022. The Author(s).)