A 2-year prospective evaluation of the Prostate Health Index in guiding biopsy decisions in a large cohort.

OBJECTIVES: To prospectively evaluate how the Prostate Health Index (PHI) impacts on clinical decision in a real-life setting for men with a prostate-specific antigen (PSA) level between 4 and 10 ng/mL and normal digital rectal examination. PATIENTS AND METHODS: Since 2016, the PHI has been available at no cost to eligible men in all Hong Kong public hospitals. All eligible patients who received PHI testing in all public Urology units (n = 16) in Hong Kong between May 2016 and August 2017 were prospectively included and followed up. All included men had a PHI test, with its result and implications explained; the subsequent follow-up plan was then decided via shared decision-making with urologists. Patients were followed up for 2 years, with outcomes including prostate biopsy rates and biopsy findings analysed in relation to the initial PHI measurements. RESULTS: A total of 2828 patients were followed up for 2 years. The majority (82%) had PHI results in the lower risk range (score <35). Knowing the PHI findings, 83% of the patients with elevated PSA decided not to undergo biopsy. In all, 11% and 45% opted for biopsy in the PHI score <35 and ≥35 groups, respectively. The initial detection rate of International Society of Urological Pathology (ISUP) Grade Group (GG) ≥2 cancer was higher in the PHI score ≥35 group (23%) than in the PHI score <35 group (7.9%). Amongst patients with no initial positive biopsy findings, the subsequent positive biopsy rate for ISUP GG ≥2 cancer was higher in the PHI score ≥35 group (34%) than the PHI score <35 group (13%) with a median follow-up of 2.4 years. CONCLUSION: In a real-life setting, with the PHI incorporated into the routine clinical pathway, 83% of the patients with elevated PSA level decided not to undergo prostate biopsy. The PHI pathway also improved the high-grade prostate cancer detection rate when compared to PSA-driven strategies. Higher baseline PHI predicted subsequent biopsy outcome at 2 years. The PHI can serve as a tool to individualise biopsy decisions and frequency of follow-up visits.

The effect of hydrostatic pressure on lipid membrane lateral structure.

High pressure is both an environmental challenge to which deep sea biology has to adapt, and a highly sensitive thermodynamic tool that can be used to trigger structural changes in biological molecules and assemblies. Lipid membranes are amongst the most pressure sensitive biological assemblies and pressure can have a large influence on their structure and properties. In this chapter, we will explore the use of high pressure small angle X-ray diffraction and high pressure microscopy to measure and quantify changes in the lateral structure of lipid membranes under both equilibrium high pressure conditions and in response to pressure jumps.

Comparing the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone.

INTRODUCTION: Cocaine is commonly consumed with ethanol, which leads to the formation of cocaethylene through transesterification. Cocaethylene is an active metabolite of cocaine with a longer duration of action. Literature on the combined toxicity of cocaine, ethanol, and cocaethylene is conflicting. We aimed to compare the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone in Hong Kong. METHODS: This was a retrospective study on acute cocaine toxicities reported to the Hong Kong Poison Control Center from 1 January 2010 to 22 January 2023. Cocaine exposure was confirmed by urine immunoassays/laboratory tests and ethanol co-ingestion was confirmed by blood ethanol concentrations. A serious outcome was defined as a National Poison Data System outcome moderate or above. Univariate analyses and multivariable logistic regression were performed to compare the associations of clinical outcomes with and without ethanol, followed by subgroup analyses of cases with complete data. RESULTS: We analyzed 109 patients (median age 29 years, 71% men, 68% Chinese), of whom 20 had confirmed ethanol co-ingestion (mean blood ethanol concentration 1350 mg/L). Multivariable analysis showed that co-exposure to cocaine and ethanol was associated with a lower risk of serious outcomes (adjusted odds ratio 0.09, 95% confidence interval 0.01-0.77; p = 0.03) after adjusting for age, sex, ethnicity, route of cocaine administration, and physical health status. Subgroup analyses showed similar findings. CONCLUSIONS: In contrast to previous studies, we did not identify a higher risk of serious outcomes after co-exposure to cocaine and ethanol compared to cocaine alone in a predominantly Chinese cohort.

Research progress on sexual functioning and associated factors in childhood cancer survivors: a scoping review.

Background: Childhood Cancer Survivors (CCSs) are more likely to report sexual dysfunction than people without cancer history. Sexual functioning encompasses more than just sexual dysfunction. The scarcity of information regarding the status and influencing factors of sexual functioning in CCSs, hampers to devise suitable screening or interventions. This review aims to summarize research progress on sexual functioning and associated factors among CCSs. Methods: This review protocol is registered in PROSPERO(CRD42023427939) and performed according to PRISMA guidelines. From inception to November 15, 2023, a comprehensive search was conducted in PubMed, EMBASE, CINAHL, Web of Science, SCOPUS, PsycINFO, CNKI Database, Wanfang of Chinese Database, SinoMed Database and Cochrane Library on sexual functioning and childhood cancer survivors. Inclusion criteria were English or Chinese studies focusing on sexual functioning and related factors of cancer survivors, who diagnosed with cancer before 18 years old, and were adult and disease-free when participating in the study. Studies were excluded if the focus was on adult cancer patients or without age information. Findings: 395 records were retrieved, and 22 studies were finally included in this review. Results suggest that CCSs experience a substantial burden of sexual issues, including delayed psychosexual development, low satisfaction, and high prevalence of dysfunction. Underlying factors related to sexual functioning of CCSs were identified, including demographic, cancer treatment-related, psychological, and physiological factors. The historical change in research on sexual functioning was summarized. Interpretation: Research on sexual functioning among CCSs is limited. The extent to which cancer and related treatments affect sexual functioning remains largely unknown. The relationships between various factors and mechanisms underlying sexual functioning need to be confirmed by more rigorous studies to enable effective interventions to be developed. Funding: None.

Suicidal ideation among non-physician hospital system staff: Prevalence and workplace correlates.

BACKGROUND: Research suggests that healthcare workers are at greater risk for suicide than other occupations, but most published studies focus on physicians. This study examines the prevalence of suicidal ideation (SI) and associated occupational factors among a broad group of non-physician healthcare staff. METHODS: An anonymous online survey was sent to a random sample of 30 % of non-physician healthcare staff at a large urban healthcare system between September and November 2022. Weighted multivariable binary logistic regressions were conducted to determine the workplace and mental health factors associated with SI. RESULTS: The 1084 respondents included nurses, administrative staff, research staff, medical assistants, nurse practitioners, physician assistants, and other roles. Of the sample, 8.8 % endorsed having SI over the prior two weeks. Results of the regression indicated that, after adjusting for demographic factors, greater odds of SI were associated with physical violence experienced from a patient or visitor (odds ratio [OR] = 2.15, 95 % confidence interval [CI] = 1.06-4.37), lower perceived leadership support (OR = 0.95, 95 % CI = 0.92-0.98), and positive screening for depression (OR = 4.66, 95 % CI = 2.45-8.86). Exploratory analysis suggests that depression may be a mediating factor between workplace stressors and SI. LIMITATIONS: Limitations include the response rate, the use of a single item to assess SI, and the cross-sectional design. CONCLUSION: Findings suggest that workplace violence and leadership support are important occupational factors associated with SI among healthcare workers. Reducing and mitigating workplace violence, enhancing leadership support, and improving access to mental health care should be considered targets for interventions to decrease suicide risk in this population.

Split ring hole metamaterial-enhanced pyroelectric detector for efficient multi-narrowband terahertz detection.

Derived from infrared pyroelectric detection, typical terahertz (THz) pyroelectric detectors have low sensitivity at low-frequency THz bands. Based on the high-efficiency absorption of the metamaterial perfect absorber (MPA), a novel split ring hole metamaterial-enhanced pyroelectric detector is proposed to achieve efficient multi-narrowband THz detection. Using high frequency simulation software (HFSS), the dimensional parameters including ring radius, ring width, connection beam width, array period, and thickness, are optimized to enhance efficient multi-narrowband absorption. The as-optimized metamaterial-enhanced detectors are fabricated via micro-nano manufacturing technology. The voltage responsiveness and noise equivalent power of the metamaterial-enhanced detector are tested by THz focused optical path and compared with those of the typical pyroelectric detector and the simulated MPA absorptivity. The results indicate that the metamaterial-enhanced detector has a multi-narrowband detection capability at 0.245 THz, 0.295 THz, and 0.38 THz, which is close to the simulated MPA absorptivity. Compared to the typical pyroelectric detector, the split ring hole metamaterial-enhanced detector can simultaneously achieve thermal absorption, thermal conduction, and pyroelectricity in the same MPA structure, providing faster response speed above 100 Hz chopper frequency and two times higher detection sensitivity at multi-narrowband THz frequencies. This research can be used for THz sensing, absorption filtering, biological macromolecule detection, and other applications.

Ebola virus-induced eye sequelae: a murine model for evaluating glycoprotein-targeting therapeutics.

BACKGROUND: Ebola virus disease (EVD) survivors experience ocular sequelae including retinal lesions, cataracts, and vision loss. While monoclonal antibodies targeting the Ebola virus glycoprotein (EBOV-GP) have shown promise in improving prognosis, their effectiveness in mitigating ocular sequelae remains uncertain. METHODS: We developed and characterized a BSL-2-compatible immunocompetent mouse model to evaluate therapeutics targeting EBOV-GP by inoculating neonatal mice with vesicular stomatitis virus expressing EBOV-GP (VSV-EBOV). To examine the impact of anti-EBOV-GP antibody treatment on acute retinitis and ocular sequelae, VSV-EBOV-infected mice were treated with polyclonal antibodies or monoclonal antibody preparations with antibody-dependent cellular cytotoxicity (ADCC-mAb) or neutralizing activity (NEUT-mAb). FINDINGS: Treatment with all anti-EBOV-GP antibodies tested dramatically reduced viremia and improved survival. Further, all treatments reduced the incidence of cataracts. However, NEUT-mAb alone or in combination with ADCC-mAb reduced viral load in the eyes, downregulated the ocular immune and inflammatory responses, and minimized retinal damage more effectively. INTERPRETATION: Anti-EBOV-GP antibodies can improve survival among EVD patients, but improved therapeutics are needed to reduce life altering sequelae. This animal model offers a new platform to examine the acute and long-term effect of the virus in the eye and the relative impact of therapeutic candidates targeting EBOV-GP. Results indicate that even antibodies that improve systemic viral clearance and survival can differ in their capacity to reduce acute ocular inflammation, and long-term retinal pathology and corneal degeneration. FUNDING: This study was partly supported by Postgraduate Research Fellowship Awards from ORISE through an interagency agreement between the US DOE and the US FDA.

MUC1-C regulates NEAT1 lncRNA expression and paraspeckle formation in cancer progression.

The MUC1 gene evolved in mammals for adaptation of barrier tissues in response to infections and damage. Paraspeckles are nuclear bodies formed on the NEAT1 lncRNA in response to loss of homeostasis. There is no known intersection of MUC1 with NEAT1 or paraspeckles. Here, we demonstrate that the MUC1-C subunit plays an essential role in regulating NEAT1 expression. MUC1-C activates the NEAT1 gene with induction of the NEAT1_1 and NEAT1_2 isoforms by NF-κB- and MYC-mediated mechanisms. MUC1-C/MYC signaling also induces expression of the SFPQ, NONO and FUS RNA binding proteins (RBPs) that associate with NEAT1_2 and are necessary for paraspeckle formation. MUC1-C integrates activation of NEAT1 and RBP-encoding genes by recruiting the PBAF chromatin remodeling complex and increasing chromatin accessibility of their respective regulatory regions. We further demonstrate that MUC1-C and NEAT1 form an auto-inductive pathway that drives common sets of genes conferring responses to inflammation and loss of homeostasis. Of functional significance, we find that the MUC1-C/NEAT1 pathway is of importance for the cancer stem cell (CSC) state and anti-cancer drug resistance. These findings identify a previously unrecognized role for MUC1-C in the regulation of NEAT1, RBPs, and paraspeckles that has been co-opted in promoting cancer progression.

Untargeted foodomics for authenticating the organic farming of water spinach (Ipomoea aquatica).

This study aimed to conduct a comprehensive analysis of the primary and secondary metabolites of water spinach (Ipomoea aquatica) using hydrophilic interaction liquid chromatography coupled with Orbitrap high-resolution mass spectrometry (HILIC-Orbitrap-HRMS). Certified samples from two cultivars, Green stem water spinach (G) and White stem water spinach (W) cultivated using organic and conventional farming methods, were collected from the Hong Kong market. Multivariate analysis was used to differentiate water spinach of different cultivars and farming methods. We identified 12 metabolites to distinguish between G and W, 26 metabolites to identify G from organic farming and 8 metabolites to identify W from organic farming. Then, two metabolites, isorhamnetin and jasmonic acid, have been proposed to serve as biomarkers for organic farming (in both G and W). Our foodomics findings provide useful tools for improving the crop performance of water spinach under abiotic/biotic stressesand authentication of organic produce.

Association of smoking cessation with airflow obstruction in workers with silicosis: A cohort study.

BACKGROUND: Studies in general population reported a positive association between tobacco smoking and airflow obstruction (AFO), a hallmark of chronic obstructive pulmonary disease (COPD). However, this attempt was less addressed in silica dust-exposed workers. METHODS: This retrospective cohort study consisted of 4481 silicotic workers attending the Pneumoconiosis Clinic during 1981-2019. The lifelong work history and smoking habits of these workers were extracted from medical records. Spirometry was carried out at the diagnosis of silicosis (n = 4177) and reperformed after an average of 9.4 years of follow-up (n = 2648). AFO was defined as forced expiratory volume in one second (FEV1)/force vital capacity (FVC) less than lower limit of normal (LLN). The association of AFO with smoking status was determined using multivariate logistics regression, and the effect of smoking cessation on the development of AFO was evaluated Cox regression. RESULTS: Smoking was significantly associated with AFO (current smokers: OR = 1.92, 95% CI 1.51-2.44; former smokers: OR = 2.09, 95% CI 1.65-2.66). The risk of AFO significantly increased in the first 3 years of quitting smoking (OR = 1.23, 95% CI 1.02-1.47) but decreased afterwards with increasing years of cessation. Smoking cessation reduced the risk of developing AFO no matter before or after the confirmation of silicosis (pre-silicosis cessation: HR = 0.58, 95% CI 0.46-0.74; post-silicosis cessation: HR = 0.62, 95% CI 0.48-0.79). CONCLUSIONS: Smoking cessation significantly reduced the risk of AFO in the workers with silicosis, although the health benefit was not observed until 3 years of abstinence. These findings highlight the importance of early and long-term smoking cessation among silicotic or silica dust-exposed workers.

Mitochondrial defects in sporadic inclusion body myositis-causes and consequences.

Sporadic inclusion body myositis (sIBM) is a distinct subcategory of Idiopathic Inflammatory Myopathies (IIM), characterized by unique pathological features such as muscle inflammation, rimmed vacuoles, and protein aggregation within the myofibers. Although hyperactivation of the immune system is widely believed as the primary cause of IIM, it is debated whether non-immune tissue dysfunction might contribute to the disease's onset as patients with sIBM are refractory to conventional immunosuppressant treatment. Moreover, the findings that mitochondrial dysfunction can elicit non-apoptotic programmed cell death and the subsequent immune response further support this hypothesis. Notably, abnormal mitochondrial structure and activities are more prominent in the muscle of sIBM than in other types of IIM, suggesting the presence of defective mitochondria might represent an overlooked contributor to the disease onset. The large-scale mitochondrial DNA deletion, aberrant protein aggregation, and slowed organelle turnover have provided mechanistic insights into the genesis of impaired mitochondria in sIBM. This article reviews the disease hallmarks of sIBM, the plausible contributors of mitochondrial damage in the sIBM muscle, and the immunological responses associated with mitochondrial perturbations. Additionally, the potential application of mitochondrial-targeted chemicals as a new treatment strategy to sIBM is explored and discussed.

Personal exposure monitoring of fine and coarse particulate matter using exposure assessment models for elderly residents in Hong Kong.

This study investigated the determinants of personal exposures (PE) to coarse (PM2.5-10) and fine particulate matter (PM2.5) for elderly communities in Hong Kong. The mean PE PM2.5 and PM2.5-10 were 23.6 ± 10.8 and 13.5 ± 22.1 µg/m3, respectively during the sampling period. Approximately 76% of study subjects presented statistically significant differences between PE and ambient origin for PM2.5 compared to approximately 56% for PM2.5-10, possibly due to the coarse-size particles being more influenced by similar sources (road dust and construction dust emissions) compared to the PM2.5 particles. Individual PE to ambient (P/A) ratios for PM2.5 all exceeded unity (≥1), suggesting the dominant influences of non-ambient particles contributed towards total PE values. There were about 80% individual P/A ratios (≤1) for PM2.5-10, implying possible effective infiltration prevention of larger size particulate matter particles leading to dominant influences from the outdoor sources. The higher concentration of NO3- and SO42- in PM2.5-10 compared to PM2.5 suggests possible heterogeneous reactions of alkaline minerals leading to the formation of NO3- and SO42- in PM2.5-10 particles. The PE and ambient OC/EC ratios in PM2.5 (8.8 ± 3.3 and 10.4 ± 22.4, respectively) and in PM2.5-10 (6.0 ± 1.9 and 3.0 ± 1.1, respectively) suggest possible secondary formed OC from surrounding rural areas. Heterogeneous distributions (COD >0.2) between the PE and ambient concentrations were found for both the PM2.5 and PM2.5-10 samples. The calibration coefficient as the association between personal and surrogate exposure measure of PE to PM2.5 (0.84) was higher than PM2.5-10 (0.52). The findings further confirm that local sources were the dominant contributor to the coarse particles and these coefficients can potentially be used to estimate different PE to PM2.5 and PM2.5-10 conditions. A comprehensive understanding of the PE to determinants in coarse particles is essential to further reduce potential exposure misclassification.

NLRX1 Inhibits LPS-Induced Microglial Death via Inducing p62-Dependent HO-1 Expression, Inhibiting MLKL and Activating PARP-1.

The activation of microglia and the production of cytokines are key factors contributing to progressive neurodegeneration. Despite the well-recognized neuronal programmed cell death regulated by microglial activation, the death of microglia themselves is less investigated. Nucleotide-binding oligomerization domain, leucine-rich repeat-containing X1 (NLRX1) functions as a scaffolding protein and is involved in various central nervous system diseases. In this study, we used the SM826 microglial cells to understand the role of NLRX1 in lipopolysaccharide (LPS)-induced cell death. We found LPS-induced cell death is blocked by necrostatin-1 and zVAD. Meanwhile, LPS can activate poly (ADP-ribose) polymerase-1 (PARP-1) to reduce DNA damage and induce heme oxygenase (HO)-1 expression to counteract cell death. NLRX1 silencing and PARP-1 inhibition by olaparib enhance LPS-induced SM826 microglial cell death in an additive manner. Less PARylation and higher DNA damage are observed in NLRX1-silencing cells. Moreover, LPS-induced HO-1 gene and protein expression through the p62-Keap1-Nrf2 axis are attenuated by NLRX1 silencing. In addition, the Nrf2-mediated positive feedback regulation of p62 is accordingly reduced by NLRX1 silencing. Of note, NLRX1 silencing does not affect LPS-induced cellular reactive oxygen species (ROS) production but increases mixed lineage kinase domain-like pseudokinase (MLKL) activation and cell necroptosis. In addition, NLRX1 silencing blocks bafilomycin A1-induced PARP-1 activation. Taken together, for the first time, we demonstrate the role of NLRX1 in protecting microglia from LPS-induced cell death. The underlying protective mechanisms of NLRX1 include upregulating LPS-induced HO-1 expression via Nrf2-dependent p62 expression and downstream Keap1-Nrf2 axis, mediating PARP-1 activation for DNA repair via ROS- and autophagy-independent pathway, and reducing MLKL activation.

Discovery and preclinical evaluations of TQB3616, a novel CDK4-biased inhibitor.

Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178).

Rate and reasons for peritoneal dialysis dropout following haemodialysis to peritoneal dialysis switch: a systematic review and meta-analysis.

BACKGROUND: Patient experiences and survival outcomes can be influenced by the circumstances related to dialysis initiation and subsequent modality choices. This systematic review and meta-analysis aimed to explore the rate and reasons for peritoneal dialysis (PD) dropout following haemodialysis (HD) to PD switch. METHOD: This systematic review conducted searches in four databases, including Medline, PubMed, Embase, and Cochrane. The protocol was registered on PROSPERO (study ID: CRD42023405718). Outcomes included factors leading to the switch from HD to PD, the rate and reasons for PD dropout and mortality difference in two groups (PD first group versus HD to PD group). The Critical Appraisal Skills Programme (CASP) checklist and the GRADE tool were used to assess quality. RESULTS: 4971 papers were detected, and 13 studies were included. On meta-analysis, there was no statistically significant difference in PD dropout in the PD first group (OR: 0.81; 95%CI: 0.61, 1.09; I2 = 83%; P = 0.16), however, there was a statistically significant reduction in the rate of mortality (OR: 0.48; 95%CI: 0.25, 0.92; I2 = 73%; P = 0.03) compared to the HD to PD group. The primary reasons for HD to PD switch, included vascular access failure, patient preference, social issues, and cardiovascular disease. Causes for PD dropout differed between the two groups, but inadequate dialysis and peritonitis were the main reasons for PD dropout in both groups. CONCLUSION: Compared to the PD first group, a previous HD history may not impact PD dropout rates for patients, but it could impact mortality in the HD to PD group. The reasons for PD dropout differed between the two groups, with no statistical differences. Psychosocial reasons for PD dropout are valuable to further research. Additionally, establishing a consensus on the definition of PD dropout is crucial for future studies.

Prenatal delta-9-tetrahydrocannabinol exposure alters fetal neurodevelopment in rhesus macaques.

Prenatal cannabis use is associated with adverse offspring neurodevelopmental outcomes, however the underlying mechanisms are relatively unknown. We sought to determine the impact of chronic delta-9-tetrahydrocannabinol (THC) exposure on fetal neurodevelopment in a rhesus macaque model using advanced imaging combined with molecular and tissue studies. Animals were divided into two groups, control (n = 5) and THC-exposed (n = 5), which received a daily THC edible pre-conception and throughout pregnancy. Fetal T2-weighted MRI was performed at gestational days 85 (G85), G110, G135 and G155 to assess volumetric brain development. At G155, animals underwent cesarean delivery with collection of fetal cerebrospinal fluid (CSF) for microRNA (miRNA) studies and fetal tissue for histologic analysis. THC exposure was associated with significant age by sex interactions in brain growth, and differences in fetal brain histology suggestive of brain dysregulation. Two extracellular vesicle associated-miRNAs were identified in THC-exposed fetal CSF; pathway analysis suggests that these miRNAs are associated with dysregulated axonal guidance and netrin signaling. This data is indicative of subtle molecular changes consistent with the observed histological data, suggesting a potential role for fetal miRNA regulation by THC. Further studies are needed to determine whether these adverse findings correlate with long-term offspring neurodevelopmental health.

Perioral Paresthesia, Generalize Muscle Cramps, and Rhabdomyolysis After a Socotra Island Blue Baboon Tarantula (Monocentropus Balfouri) Bite.

BACKGROUND: Literature on systemic envenomation caused by tarantula bites, particularly from the Theraphosidae family, is relatively scarce. This case report provides a formal description of the first known instance of systemic envenomation caused by the Socotra Island Blue Baboon Tarantula (Monocentropus balfouri). CASE REPORT: In this case, a 23-year-old employee of an exotic pet shop suffered from perioral paresthesia, generalized muscle cramps, and rhabdomyolysis because of a Monocentropus balfouri bite. His symptoms were successfully relieved with oral benzodiazepines. EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the potential for serious complications resulting from the bite of Monocentropus balfouri, a species gaining popularity among global exotic pet collectors.