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Abstract Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer’s disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P

Abstract Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Antibiotic resistant bacteria (ARB) with antibiotic resistance genes (ARGs) can reduce or eliminate the effectiveness of antibiotics and thus threaten human health. The United Nations Environment Programme considers antibiotic resistance the first of six emerging issues of concern. Advanced oxidation processes (AOPs) that combine ultraviolet (UV) irradiation and chemical oxidation (primarily chlorine, hydrogen peroxide, and persulfate) have attracted increasing interest as advanced water and wastewater treatment technologies. These integrated technologies have been reported to significantly elevate the efficiencies of ARB inactivation and ARG degradation compared with direct UV irradiation or chemical oxidation alone due to the generation of multiple reactive species. In this study, the performance and underlying mechanisms of UV/chlorine, UV/hydrogen peroxide, and UV/persulfate processes for controlling ARB and ARGs were reviewed based on recent studies. Factors affecting the process-specific efficiency in controlling ARB and ARGs were discussed, including biotic factors, oxidant dose, UV fluence, pH, and water matrix properties. In addition, the cost-effectiveness of the UV-based AOPs was evaluated using the concept of electrical energy per order. The UV/chlorine process exhibited a higher efficiency with lower energy consumption than other UV-based AOPs in the wastewater matrix, indicating its potential for ARB inactivation and ARG degradation in wastewater treatment. Further studies are required to address the trade-off between toxic byproduct formation and the energy efficiency of the UV/chlorine process in real wastewater to facilitate its optimization and application in the control of ARB and ARGs.

Abstract Background Many ethnic minorities in Hong Kong seek medical tourism after encountering inequalities in access to local healthcare because of language barriers and cultural-religious differences. The present study explored the ethnic minorities’ lived experiences of medical tourism and issues arising from cross-border health-seeking relevant to this specific population. Methods Qualitative in-depth interviews with 25 ethnic minority informants from five South Asian countries in 2019. Results The 19 informants out of the 25 have sought assistance from their international networks for home remedies, medical advice and treatments of traditional/Western medicines, for they are more costly or unavailable in Hong Kong and for issues related to racial discrimination, language barriers, transnationalism engagement, cultural insensitivity, and dissatisfaction with healthcare services in Hong Kong. Discussion Medical tourism can relieve the host country’s caring responsibilities from healthcare services, so the government might no longer be hard-pressed to fix the failing healthcare system. Consequently, it could cause public health concerns, such as having patients bear the risks of exposure to new pathogens, the extra cost from postoperative complications, gaps in medical documentation and continuum of care, etc. It also triggers global inequities in health care, exacerbating unequal distribution of resources among the affordable and non-affordable groups. Conclusion Ethnic minorities in Hong Kong sought cross-border healthcare because of structural and cultural-religious issues. The surge of medical tourism from rich and developed countries to poor and developing countries may infringe upon the rights of residents in destination countries. To mitigate such negative impacts, policymakers of host countries should improve hospital infrastructure, as well as train and recruit more culturally sensitive healthcare workers to promote universal health coverage. Healthcare professionals should also strive to enhance their cultural competence to foster effective intercultural communication for ethnic minority groups.

Input of pollutants to estuaries is one of the major threats to marine biodiversity and fishery resources, and pharmaceuticals are one of the most important contaminants of emerging concern in aquatic ecosystems. To synthesize pharmaceutical pollution levels in estuaries over the past 20 years from a global perspective, this review identified 3229 individual environmental occurrence data for 239 pharmaceuticals across 91 global estuaries distributed in 26 countries. The highest cumulative weighted average concentration level (WACL) of all detected pharmaceuticals in estuarine water was observed in Africa (145,461.86 ng/L), with 30 pharmaceuticals reported. North America (24,316.39 ng/L) was ranked second in terms of WACL, followed by South America (20,784.13 ng/L), Asia (5958.38 ng/L), Europe (4691.23 ng/L), and Oceania (2916.32 ng/L). Carbamazepine, diclofenac, and paracetamol were detected in all continents. A total of 41 functional categories of pharmaceuticals were identified, and analgesics, antibiotics, and stimulants were amongst the most ubiquitous groups in estuaries worldwide. Although many pharmaceuticals were observed to present lower than or equal to moderate ecological risk, 34 pharmaceuticals were identified with high or very high ecological risks in at least one continent. Pharmaceutical pollution in estuaries was positively correlated with regional unemployment and poverty ratios, but negatively correlated with life expectancy and GDP per capita. There are some limitations that may affect this synthesis, such as comparability of the sampling and pretreatment methodology, differences in the target pharmaceuticals for monitoring, and potentially limited number and diversity of estuaries covered, which prompt us to standardize methods for monitoring these pharmaceutical contaminants in future global studies.

ABSTRACT The environmental DNA (eDNA) approach is an emerging tool for monitoring marine biodiversity. However, the sampling effort needs optimization according to the site characteristics and target taxonomic groups. In this study, we optimized the eDNA sampling effort in terms of sample volume and number of replicates to monitor the diversity of marine vertebrates (mainly fish) in Hong Kong's subtropical waters that show a gradient of estuarine to oceanic waters. To maximize detection, we used three pairs of metabarcoding primers (12S‐v5, MiFish‐U, and MiFish‐E). We compared vertebrate diversity in 78 water samples, ranging from 1 to 10 L, collected from oceanic and estuarine sites. Metabarcoding yielded a total of 140 vertebrate species, of which 18 were unique to the estuarine site, 66 unique to the oceanic site, and 56 shared between both sites. The detected species were predominantly ray‐finned fish (136 species), and the three primer pairs exhibited differential sensitivity toward different taxa, especially cartilaginous fish and cetaceans. Increasing sampling volume per replicate generally increased the total detected species, average species per replicate, and species coverage, and sampling 3 or 4 × 4 L represented the most efficient sampling effort for the estuarine and oceanic sites, respectively. The diversity analysis revealed that sampling >2 L per replicate reduced variability and improved diversity analysis. The results also showed that a larger sampling volume per replicate increased the probability of detecting endangered, indicator, invasive, and elusive species, with 4 L representing the most efficient volume. This study recommended sampling 4 L per replicate and 3 replicates for estuarine and 4 for oceanic sites, respectively for effectively monitoring marine fish in subtropical waters using the eDNA approach.

Marine protected areas are set up across the globe to safeguard biodiversity and support coastal ecosystem functioning. In Hong Kong, partially protected marine parks and a no-take marine reserve have been managed under legislation for years, yet a comprehensive evaluation of their conservation impact is still pending despite the region’s reputation for high marine diversity. Most studies assess conservation effectiveness solely in terms of taxonomic diversity, without delving into the contributions of functional and phylogenetic diversity. In this study, we used environmental DNA combined with multifaceted diversity indicators to assess the impact of the level of protection on the fish community in Hong Kong waters. Our results indicated that the marine protected areas significantly contributed to fish community conservation. The no-take marine reserve exhibited the highest taxonomic and phylogenetic diversity, while partially protected marine parks showed the most balanced community composition. No significant increase in fish functional diversity was found in the protected areas. Water quality, hydrological condition, and protection level were the primary factors affecting community variation for taxonomic, functional, and phylogenetic diversity, respectively. Fish species composition significantly varied with different protection levels, and species turnover was the main component of the dissimilarity. Future management of marine protected areas should assess multifaceted biological indicators and establish a rational conservation scheme.

Abstract Background DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are “non-atopic”, lacking a clear etiology. Methods In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman’s rank correlation coefficients, multiple logistic regression, and multinomial logistic regression. Results Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified. Conclusion The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies.

Abstract The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer’s Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community.

Abstract Background Short tandem repeats (STRs) are widely distributed across the human genome and are associated with numerous neurological disorders. However, the extent that STRs contribute to disease is likely under-estimated because of the challenges calling these variants in short read next generation sequencing data. Several computational tools have been developed for STR variant calling, but none fully address all of the complexities associated with this variant class. Results Here we introduce LUSTR which is designed to address some of the challenges associated with STR variant calling by enabling more flexibility in defining STR loci, allowing for customizable modules to tailor analyses, and expanding the capability to call somatic and multiallelic STR variants. LUSTR is a user-friendly and easily customizable tool for targeted or unbiased genome-wide STR variant screening that can use either predefined or novel genome builds. Using both simulated and real data sets, we demonstrated that LUSTR accurately infers germline and somatic STR expansions in individuals with and without diseases. Conclusions LUSTR offers a powerful and user-friendly approach that allows for the identification of STR variants and can facilitate more comprehensive studies evaluating the role of pathogenic STR variants across human diseases.

Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and deprotection. These depolymerases are enzymes responsible for degrading diverse bacterial surface carbohydrates. They are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance, making them an invaluable asset in the era of antibiotic resistance. Numerous depolymerases have been investigated preclinically, with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection models. Additionally, some formulation approaches have been developed for improved stability and activity of depolymerases. However, depolymerase formulation is limited to liquid dosage form and remains in its infancy, posing a significant hurdle to their clinical translation, compounded by challenges in their applicability and manufacturing. Future development must address these obstacles for clinical utility. Here, after unravelling the history, diversity, and therapeutic use of depolymerases, we summarized the preclinical efficacy and existing formulation findings of recombinant depolymerases. Finally, the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development.

Abstract Respiratory Staphylococcus aureus infection represents a common complication in lung cancer patients, which is characterized with progressively and recurrently intratumor invasion. Although bacteriophages are widely reported as an effective bioweapon for managing bacterial infections, its applicability in handling infectious complications during cancer chemotherapy remains unknown. In this work, we hypothesized cancer chemotherapeutics would influence the efficacy of bacteriophages. To verify this end, interactions between four anticancer drugs (Gemcitabine, Doxorubicin, Cisplatin, and Irinotecan) with phage K were investigated, where Cisplatin directly reduced phage titers while Gemcitabine and Doxorubicin partially inhibited its propagation. The antibacterial efficacy of drug-phage K combinations was tested in a S. aureus infected cancer cell model. Doxorubicin enhanced the antibacterial capacity of phage K, destroying 22-folds of cell-associated bacteria than that of phage K alone use. Also, S. aureus migration was remarkably reduced by Doxorubicin. Overall, our data suggested that Doxorubicin had synergistic effects with phage K in combating S. aureus intracellular infection and migration. This work may broaden the options of indication for phage clinical transformation and also provide reference for the adjunctive application of chemo drugs in intracellular infection management.

Abstract Background Alzheimer’s disease (AD) shares risk factors with cardiovascular disease (CVD) and dysregulated cholesterol metabolism is a mechanism common to both diseases. Cholesterol efflux capacity (CEC) is an ex vivo metric of plasma high-density lipoprotein (HDL) function and inversely predicts incident CVD independently of other risk factors. Cholesterol pools in the central nervous system (CNS) are largely separate from those in blood, and CNS cholesterol excess may promote neurodegeneration. CEC of cerebrospinal fluid (CSF) may be a useful measure of CNS cholesterol trafficking. We hypothesized that subjects with AD and mild cognitive impairment (MCI) would have reduced CSF CEC compared with Cognitively Normal (CN) and that CSF apolipoproteins apoA-I, apoJ, and apoE might have associations with CSF CEC. Methods We retrieved CSF and same-day ethylenediaminetetraacetic acid (EDTA) plasma from 108 subjects (40 AD; 18 MCI; and 50 CN) from the Center for Neurodegenerative Disease Research biobank at the Perelman School of Medicine, University of Pennsylvania. For CSF CEC assays, we used N9 mouse microglial cells and SH-SY5Y human neuroblastoma cells, and the corresponding plasma assay used J774 cells. Cells were labeled with [3H]-cholesterol for 24 h, had ABCA1 expression upregulated for 6 h, were exposed to 33 μl of CSF, and then were incubated for 2.5 h. CEC was quantified as percent [3H]-cholesterol counts in medium of total counts medium+cells, normalized to a pool sample. ApoA-I, ApoJ, ApoE, and cholesterol were also measured in CSF. Results We found that CSF CEC was significantly lower in MCI compared with controls and was poorly correlated with plasma CEC. CSF levels of ApoJ/Clusterin were also significantly lower in MCI and were significantly associated with CSF CEC. While CSF ApoA-I was also associated with CSF CEC, CSF ApoE had no association with CSF CEC. CSF CEC is significantly and positively associated with CSF Aβ. Taken together, ApoJ/Clusterin may be an important determinant of CSF CEC, which in turn could mitigate risk of MCI and AD risk by promoting cellular efflux of cholesterol or other lipids. In contrast, CSF ApoE does not appear to play a role in determining CSF CEC.

Abstract Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration in nigrostriatal and cortical brain regions associated with pathogenic α-synuclein (αSyn) aggregate/oligomer accumulation. LRRK2 hyperactivity is a disease-modifying therapeutic target in PD. However, LRRK2 inhibition may be associated with peripheral effects, albeit with unclear clinical consequences. Here, we significantly reduced αSyn oligomer accumulation in mouse striatum through long-term LRRK2 inhibition using GNE-7915 (specific brain-penetrant LRRK2 inhibitor) without causing adverse peripheral effects. GNE-7915 concentrations in wild-type (WT) mouse sera and brain samples reached a peak at 1 h, which gradually decreased over 24 h following a single subcutaneous (100 mg/kg) injection. The same dose in young WT and LRRK2R1441G mutant mice significantly inhibited LRRK2 kinase activity (Thr73-Rab10 and Ser106-Rab12 phosphorylation) in the lung, which dissipated by 72 h post-injection. 14-month-old mutant mice injected with GNE-7915 twice weekly for 18 weeks (equivalent to ~13 human years) exhibited reduced striatal αSyn oligomer and cortical pSer129-αSyn levels, correlating with inhibition of LRRK2 hyperactivity in brain and lung to WT levels. No GNE-7915-treated mice showed increased mortality or morbidity. Unlike reports of abnormalities in lung and kidney at acute high doses of LRRK2 inhibitors, our GNE-7915-treated mice did not exhibit swollen lamellar bodies in type II pneumocytes or abnormal vacuolation in the kidney. Functional and histopathological assessments of lung, kidney and liver, including whole-body plethysmography, urinary albumin-creatinine ratio (ACR), serum alanine aminotransferase (ALT) and serum interleukin-6 (inflammatory marker) did not reveal abnormalities after long-term GNE-7915 treatment. Long-term inhibition of mutant LRRK2 hyper-kinase activity to physiological levels presents an efficacious and safe disease-modifying therapy to ameliorate synucleinopathy in PD.

Aim: We aimed to report the epidemiology of OHCA, bystander CPR pattern and other Utstein factors in a region in Hong Kong during the COVID-19 pandemic. In particular, we studied the relationship between COVID-19 incidence, OHCA incidence and survival outcome. Methods: This was a retrospective cohort study that used data from our registry to compare features of OHCA during pre-pandemic (Jan 2018 to Dec 2019), low-incidence pandemic (Jan 2020 to Dec 2021) and high-incidence pandemic (Jan to Mar 2022). We used multivariable logistic regression to identify survival predictors. Results: Incidence of OHCA increased dramatically with surging COVID-19 incidence (65.9 vs 74.2 vs 159.2 per 100,000 population per year, p

Aims With the ageing population, fragility fractures have become one of the most common conditions. The objective of this study was to investigate whether microbiological outcomes and fracture-healing in osteoporotic bone is worse than normal bone with fracture-related infection (FRI). Methods A total of 120 six-month-old Sprague-Dawley (SD) rats were randomized to six groups: Sham, sham + infection (Sham-Inf), sham with infection + antibiotics (Sham-Inf-A), ovariectomized (OVX), OVX + infection (OVX-Inf), and OVX + infection + antibiotics (OVX-Inf-A). Open femoral diaphysis fractures with Kirschner wire fixation were performed. Staphylococcus aureus at 4 × 104 colony-forming units (CFU)/ml was inoculated. Rats were euthanized at four and eight weeks post-surgery. Radiography, micro-CT, haematoxylin-eosin, mechanical testing, immunohistochemistry (IHC), gram staining, agar plating, crystal violet staining, and scanning electron microscopy were performed. Results Agar plating analysis revealed a higher bacterial load in bone (p = 0.002), and gram staining showed higher cortical bone colonization (p = 0.039) in OVX-Inf compared to Sham-Inf. OVX-Inf showed significantly increased callus area (p = 0.013), but decreased high-density bone volume (p = 0.023) compared to Sham-Inf. IHC staining showed a significantly increased expression of TNF-α in OVX-Inf compared to OVX (p = 0.049). Significantly reduced bacterial load on bone (p = 0.001), enhanced ultimate load (p = 0.001), and energy to failure were observed in Sham-Inf-A compared to Sham-Inf (p = 0.028), but not in OVX-Inf-A compared to OVX-Inf. Conclusion In osteoporotic bone with FRI, infection was more severe with more bone lysis and higher bacterial load, and fracture-healing was further delayed. Systemic antibiotics significantly reduced bacterial load and enhanced callus quality and strength in normal bone with FRI, but not in osteoporotic bone. Cite this article: Bone Joint Res 2022;11(2):49–60.

The coronavirus disease 2019 (COVID-19) pandemic is challenging the current public health emergency response systems (PHERSs) of many countries. Although environmental factors, such as those influencing the survival of viruses and their transmission between species including humans, play important roles in PHERSs, little attention has been given to these factors. This study describes and elucidates the roles of environmental factors in future PHERSs. To improve countries’ capability to respond to public health emergencies associated with viral infections such as the COVID-19 pandemic, a number of environmental factors should be considered before, during, and after the responses to such emergencies. More specifically, to prevent pandemic outbreaks, we should strengthen environmental and wildlife protection, conduct detailed viral surveillance in animals and hotspots, and improve early-warning systems. During the pandemic, we must study the impacts of environmental factors on viral behaviors, develop control measures to minimize secondary environmental risks, and conduct timely assessments of viral risks and secondary environmental effects with a view to reducing the impacts of the pandemic on human health and on ecosystems. After the pandemic, we should further strengthen surveillance for viruses and the prevention of viral spread, maintain control measures for minimizing secondary environmental risks, develop our capability to scientifically predict pandemics and resurgences, and prepare for the next unexpected resurgence. Meanwhile, we should restore the normal life and production of the public based on the “One Health” concept, that views global human and environmental health as inextricably linked. Our recommendations are essential for improving nations’ capability to respond to global public health emergencies.

Coastal eutrophication and hypoxia remain a persistent environmental crisis despite the great efforts to reduce nutrient loading and mitigate associated environmental damages. Symptoms of this crisis have appeared to spread rapidly, reaching developing countries in Asia with emergences in Southern America and Africa. The pace of changes and the underlying drivers remain not so clear. To address the gap, we review the up-to-date status and mechanisms of eutrophication and hypoxia in global coastal oceans, upon which we examine the trajectories of changes over the 40 years or longer in six model coastal systems with varying socio-economic development statuses and different levels and histories of eutrophication. Although these coastal systems share common features of eutrophication, site-specific characteristics are also substantial, depending on the regional environmental setting and level of social-economic development along with policy implementation and management. Nevertheless, ecosystem recovery generally needs greater reduction in pressures compared to that initiated degradation and becomes less feasible to achieve past norms with a longer time anthropogenic pressures on the ecosystems. While the qualitative causality between drivers and consequences is well established, quantitative attribution of these drivers to eutrophication and hypoxia remains difficult especially when we consider the social economic drivers because the changes in coastal ecosystems are subject to multiple influences and the cause–effect relationship is often non-linear. Such relationships are further complicated by climate changes that have been accelerating over the past few decades. The knowledge gaps that limit our quantitative and mechanistic understanding of the human-coastal ocean nexus are identified, which is essential for science-based policy making. Recognizing lessons from past management practices, we advocate for a better, more efficient indexing system of coastal eutrophication and an advanced regional earth system modeling framework with optimal modules of human dimensions to facilitate the development and evaluation of effective policy and restoration actions.

Camptothecin derivatives are precursors of potent anticancer agents, but their biosynthesis remains largely unknown. Here two cytochrome P450 monooxygenases are shown to regiospecifically oxidize camptothecin, yielding 10- and 11- hydroxylated derivatives, which are subsequently used to produce a suite of known anticancer drugs and derivatives.

Penetrating traumatic brain injury (pTBI) often occurs with systemic insults such as hemorrhagic shock (HS) and hypoxemic (HX). This study examines rat models of penetrating ballistic-like brain injury (PBBI) and HX+HS to assess whether the blood levels of brain and systemic response biomarkers phosphorylated neurofilament-heavy protein (pNF-H), neurofilament-light protein (NF-L), ?II-spectrin, heat shock protein (HSP70), and high mobility group box 1 protein (HMGB1) can distinguish pTBI from systemic insults and guide in pTBI diagnosis, prognosis, and monitoring. Thirty rats were randomly assigned to sham, PBBI, HS+HX, and PBBI+HS+HX groups. PBBI and sham groups underwent craniotomy with and without probe insertion and balloon expansion, respectively. HX and HS was then simulated by blood withdrawal and fraction of inspired oxygen (FIO2) reduction. Biomarker serum concentrations were determined at one (D1) and two (D2) days post-injury with enzyme-linked immunosorbent assay (ELISA) methods. Axonal injury-linked biomarkers pNF-H and NF-L serum levels in PBBI groups were higher than those in sham and HX+HS groups at D1 and D2 post-injury. The same was true for PBBI+HX+HS compared with sham (D2 only for pNF-H) and HX+HS groups. However, pNF-H and NF-L levels in PBBI+HX+HS groups were not different than their PBBI counterparts. At D1, ?II-spectrin levels in the HX+HS and PBBI+HS+HX groups were higher than the sham groups. ?II-spectrin levels in the HX+HS group were higher than the PBBI group. This suggests HX+HS as the common insult driving ?II-spectrin elevations. In conclusion, pNF-H and NF-L may serve as specific serum biomarkers of pTBI in the presence or absence of systemic insults. ?II-spectrin may be a sensitive acute biomarker in detecting systemic insults occurring alone or with pTBI.

Objectives: This study aims to explore the role of M2a polarization and formyl peptide receptor (FPR) regulation in the reactivation of Mycobacterium tuberculosis (Mtb) infection. Methods: M1/M2a monocyte percentage and FPR1/2/3 protein expression of blood immune cells were measured in 38 patients with sputum culture (+) active pulmonary TB disease, 18 subjects with latent TB infection (LTBI), and 28 noninfected healthy subjects (NIHS) using flow cytometry method. Results: M1 percentage was decreased in active TB versus either NIHS or LTBI group, while M2a percentage and M2a/M1 percentage ratio were increased. FPR1 expression on M1/M2a, FPR2 expression on M1, and FPR3 expression of M1 were all decreased in active TB versus LTBI group, while FPR1 over FPR2 expression ratio on NK T cell was increased in active TB versus either NIHS or LTBI group. In 11 patients with active TB disease, M1 percentage became normal again after anti-TB treatment. In vitro Mtb-specific antigen stimulation of monocytic THP-1 cells resulted in M2a polarization in association with increased FPR2 expression on M2a. Conclusions: Increased M2a and decreased M1 phenotypes of blood monocyte may serve as a marker for active TB disease, while decreased FPR1 on blood monocyte may indicate LTBI status.

Being a class of vitamin A’s main derivatives, retinoic acids (RAs) are important to animals’ growth and development. Previous studies demonstrated that exposure of excessive amounts of RAs would lead to malformation and abnormal development in aquatic animals such as amphibians and fishes. Currently, there are only limited toxicity data of RAs available for freshwater species, while those for marine species are seriously lacking. This study aimed to fill such data gap by conducting toxicity tests on six marine species (i.e., one microalga, four invertebrates and one fish) towards the exposure to all-trans-RA (at-RA), which is the most widely distributed RA in the environment. Results showed that the embryo of medaka fish Oryzias melastigma was the most sensitive towards the exposure of at-RA while the gastropod Monodonta labio was the least sensitive. A species sensitivity distribution (SSD) was constructed based on the experimental results generated from the present study. An interim marine-specific predicted no-effect concentration (PNEC) of at-RA was derived at 2300 ng/L. By computing the hazard quotients using the interim marine-specific PNEC and available measured and predicted concentrations of RAs, we found the current levels of RAs posed no immediate risks to the marine environment of Hong Kong. The interim marine-specific PNEC was more than 500-fold of freshwater-specific PNEC (i.e., 3.93 ng/L), indicating that marine species were generally less sensitive than their freshwater counterparts towards RAs. This was the first study to document the concentration-response of various marine species towards at-RA exposure and construct the marine-specific SSD for assessing the ecological risk of at-RA towards the marine environment. Since various forms of RAs and their metabolites often coexist in aquatic environments, further studies should investigate their combined toxicity to an array of marine species of different trophic levels with consideration of chronic exposure scenarios.

Recent high-throughput structure-sensitive genome-wide sequencing-based assays have enabled large-scale studies of RNA structure, and robust transcriptome-wide computational prediction of individual RNA structures across RNA classes from these assays has potential to further improve the prediction accuracy. Here, we describe HiPR, a novel method for RNA structure prediction at single-nucleotide resolution that combines high-throughput structure probing data (DMS-seq, DMS-MaPseq) with a novel probabilistic folding algorithm. On validation data spanning a variety of RNA classes, HiPR often increases accuracy for predicting RNA structures, giving researchers new tools to study RNA structure.

Alzheimer’s Disease (AD) is a progressive neurologic disease and the most common form of dementia. While the causes of AD are not completely understood, genetics plays a key role in the etiology of AD, and thus finding genetic factors holds the potential to uncover novel AD mechanisms. For this study, we focus on copy number variation (CNV) detection and burden analysis. Leveraging whole-genome sequence (WGS) data released by Alzheimer’s Disease Sequencing Project (ADSP), we developed a scalable bioinformatics pipeline to identify CNVs. This pipeline was applied to 1,737 AD cases and 2,063 cognitively normal controls. As a result, we observed 237,306 and 42,767 deletions and duplications, respectively, with an average of 2,255 deletions and 1,820 duplications per subject. The burden tests show that Non-Hispanic-White cases on average have 16 more duplications than controls do (p-value 2e-6), and Hispanic cases have larger deletions than controls do (p-value 6.8e-5).

Discharge of partially treated effluent from sewage treatment plants (STPs) is a significant source of chemical contaminants, such as retinoids and oestrogenic endocrine disrupting chemicals (EDCs), which are continuously input into the marine environments of densely populated and urbanized coastal cities. In this study, we successfully developed three analytical methods to detect and qualify retinoic acids (at-RA, 13c-RA & 9c-RA), their metabolites (at-4-oxo-RA, 13c-4-oxo-RA & 9c-4-oxo-RA), and oestrogenic EDCs using high pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Using these methods, we found that the total concentrations of retinoids in the influents and effluents of three saline STPs in Hong Kong were 7.1–29 ng/L and 3.7–9.1 ng/L, respectively, and those of EDCs were 3107–5829 ng/L and 1225–2638 ng/L, respectively. Retinoids were dominated by at-4-oxo-RA or 13c-4-oxo-RA in wastewater, whereas at-RA and 13c-RA were the most abundant in sludge. Alkylphenols and bisphenol A were the dominant EDCs in wastewater, whilst alkylphenols, triclosan, and triclocarban were dominant in sludge. Overall, the sewage treatment processes in the STPs of Hong Kong were not highly efficient in the removal of retinoids and EDCs from wastewater influents, with removal efficiencies in the aqueous phase of 41–82% and 31–79%, respectively. The removals were attributed mainly to sorption and degradation. Due to such limited removal, the effluents from STPs and the adjacent seawaters (i.e., receiving water bodies) still exhibited relatively high concentrations of retinoids (2.0–4.3 ng/L in seawaters) and EDCs (71–260 ng/L in seawaters), which posed medium ecological risks to the coastal marine ecosystem of Hong Kong (i.e., hazard quotients: 0.1–1). Keywords: Retinoids, Endocrine disrupting chemicals, Sewage, Seawater, Risk assessment, Marine organisms

The multi-inlet vortex mixer (MIVM) has emerged as a novel bottom-up technology for solid nanoparticle preparation. However, its performance in liposome preparation remains unknown. Here, two key process parameters (aqueous/organic flow rate ratio (FRR) and total flow rate (TFR)) of MIVM were investigated for liposome preparation. For this study, two model drugs (lysozyme and erythromycin) were chosen for liposome encapsulation as the representative hydrophilic and hydrophobic drugs, respectively. In addition, two modified MIVMs, one with herringbone-patterned straight inlets and one with zigzag inlets, were designed to further improve the mixing efficiency, aiming to achieve better drug encapsulation. Data showed that FRR played an important role in liposome size control, and a size of

With the advancement of technology, drug delivery systems and molecules with more complex architecture are developed. As a result, the drug absorption and disposition processes after administration of these drug delivery systems and engineered molecules become exceedingly complex. As the pharmacokinetic and pharmacodynamic (PK-PD) modeling allows for the separation of the drug-, carrier- and pharmacological system-specific parameters, it has been widely used to improve understanding of the in vivo behavior of these complex delivery systems and help their development. In this review, we summarized the basic PK-PD modeling theory in drug delivery and demonstrated how it had been applied to help the development of new delivery systems and modified large molecules. The linkage between PK and PD was highlighted. In particular, we exemplified the application of PK-PD modeling in the development of extended-release formulations, liposomal drugs, modified proteins, and antibody-drug conjugates. Furthermore, the model-based simulation using primary PD models for direct and indirect PD responses was conducted to explain the assertion of hypothetical minimal effective concentration or threshold in the exposure-response relationship of many drugs and its misconception. The limitations and challenges of the mechanism-based PK-PD model were also discussed.

The occurrence of triphenyltin (TPT) compounds, a highly toxic antifouling biocide, has been documented in marine environments and organisms all over the world. While some studies showed that marine mammals can be used as sentinel organisms to evaluate the pollution status of emerging contaminants in the environment because of their long lifespans and high trophic levels, information regarding the contamination status of TPT in marine mammal species has been limited over the past decade. More importantly, the primary bioaccumulation pathway of TPT in these long-lived apex predators and the corresponding marine food web is still uncertain. Therefore, this study aimed to evaluate the contamination statuses of TPT in two marine mammal species, namely the finless porpoise and the Indo-Pacific humpback dolphin, and assess the trophic magnification potential of TPT along the food webs of these two species, using stable isotope analysis, and chemical analysis with gas chromatography-mass spectrometry. The results showed that TPT is the predominant residue in majority of the analyzed individuals of two marine mammals, with concentrations ranging from 426.2 to 3476.6 ng/g wet weight in their muscle tissues. Our results also demonstrated an exponential increase in the concentration of TPT along the marine food web, indicating that trophic magnification occurs in the respective food webs of the two marine mammals. The range of trophic magnification factors of TPT in the food webs of finless porpoise and Indo-Pacific humpback dolphin was 2.51–3.47 and 2.45–3.39, respectively. These results suggest that high trophic organisms may be more vulnerable to the exposure of TPT-contaminated environments due to the high trophic magnification potential, and thus ecological risk of these compounds ought to be assessed with the consideration of their bioaccumulation potentials in these marine mammals. Keywords: Marine mammal, Food web, Biomagnification, Organotin compounds, Stable Isotope

In animals, retinoic acids (RAs), one of the main derivatives of vitamin A, are crucial for a variety of physiological processes. RAs, including all-trans-RA, 9-cis-RA, 13-cis-RA, and their corresponding metabolites (i.e., all-trans-4-oxo-RA, 9-cis-4-oxo-RA and 13-cis-4-oxo-RA) can be excreted through urination from humans and animals. Sewage treatment plants (STPs) are a significant source of RAs and 4-oxo-RAs into aquatic environments. RAs and 4-oxo-RAs can be identified and quantified by use of liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). RAs and 4-oxo-RAs have been reported in various environmental matrices including rivers, lakes, reservoirs and coastal marine environments as well as in sewage effluents discharged from STPs. Greater concentrations of RAs and 4-oxo-RAs have been observed during blooms of cyanobacteria and microalgae, suggesting that cyanobacteria and microalgae are natural sources of RAs and 4-oxo-RAs in aquatic environments. These potential sources of RAs and 4-oxo-RAs raise concerns about their concentrations and risks in aquatic environments because excessive intake of these chemicals can result in abnormal morphological development in animals. Teratogenic effects were observed in amphibians, fish embryos, gastropods, mammals and birds when exposed to RAs. This review summarizes sources, concentrations, adverse effects and ecological risks of RAs and 4-oxo-RAs in aquatic environments. An interim, predicted no-effect concentration (PNEC) of RAs (in terms of at-RA) for freshwater environments was determined to be 3.93 ng/L at-RA equivalents. Based on limited data on concentrations of RAs in freshwater ecosystems, their hazard quotients were found to range from zero to 16.41, depending on the environmental conditions of receiving waters. Ecological risks of RAs in marine environments are yet to be explored due to the paucity of data related to both their concentrations in marine environment and toxic potencies to marine species. This review updates current knowledge of RAs and 4-oxo-RAs in aquatic environments and calls for more studies on their concentrations and fate in aquatic environments, especially estuarine and coastal marine environments with a view to enabling a comprehensive assessment of their ecological risks around the globe. Keywords: Retinoids, Sewage, Cyanobacteria, Aquatic environments, Ecological risks, Marine

ObjectivesThis study investigates perceived barriers towards the implementation of multiprofessional team briefings (MPTB) in operating theatres, as well as ways to overcome these perceived barriers. Previous research shows that MPTB can enhance teamwork and communication, but are underused in operating theatres. By adopting a multilevel systems perspective, this study examines perceived barriers and solutions for MPTB implementation.DesignParticipants completed open-ended survey questions. Responses were coded via qualitative content analysis. The analysis focused on themes in the responses and the systems level at which each barrier and solution operates.SettingFour tertiary hospitals in Australia.Participants103 operating theatre staff, including nurses, surgeons, anaesthetists, technicians and administrators.ResultsParticipants identified barriers and solutions at the organisational (15.81% of barriers; 74.10% of solutions), work group (61.39% of barriers; 25.09% of solutions) and individual level (22.33% of barriers; 0% of solutions). Of all the perceived barriers to MPTB occurrence, a key one is getting everyone into the room at the same time . Matching of perceived barriers and solutions shows that higher systems-level solutions can address lower level barriers, thereby showing the relevance of implementing such wider reaching solutions to MPTB occurrence (including work practices at occupational level and above) as well as addressing more local issues.ConclusionsSuccessful MPTB implementation requires changes at various systems levels. Practitioners can strategically prepare and plan for systems-based strategies to overcome barriers to MPTB implementation. Future research can build on this study’s findings by directly examining higher systems-level barriers and solutions via detailed case analyses.

IntroductionGynaecological cancers collectively account for almost 10% of cancer diagnoses made in Australian women. The extent of variation in gynaecological cancer survival rates and treatment outcomes across Australia is not well documented. The purpose of the clinical quality registry described in this paper is to systematically monitor and improve quality of care provided to these women, and facilitate clinical process improvements to ensure better patient outcomes and greater adherence to best practice care. The registry infrastructure has been developed in conjunction alongside the inaugural ovarian, tubal and peritoneal (OTP) module, allowing for concurrent piloting of the methodology and one module. Additional tumour modules will be developed in time to cover the other gynaecological tumour types.Method and analysisThe National Gynae-Oncology Registry (NGOR) aims to capture clinical data on all newly diagnosed cancers of the uterus, ovary, fallopian tubes, peritoneum, cervix, vulva and vagina in Australia with a view to using these data to support improved clinical care and increased adherence to ‘best practice’. Data are sourced from existing clinical databases maintained by clinicians and/or hospital gynaecological cancer units. A pilot phase incorporating only OTP cancers has recently been conducted to assess the feasibility of the registry methodology and assess the support of a quality initiative of this nature among clinicians and other key stakeholders.Ethics and disseminationThe NGOR has received National Mutual Acceptance (NMA) ethics approval from Monash Health Human Research Ethics Committee (HREC), NMA HREC Reference Number: HREC/17/MonH/198. We also have approval from Mercy Health HREC and University of Tasmania HREC. Data will be routinely reported back to participating sites illustrating their performance against measures of agreed best practice. It is through this feedback system that the registry will support changes to quality of care and improved patient outcomes.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) pose a significant threat to global public health. In present research, a total of 80 CRKP strains belonging to ST11 were collected with 70% (56 of 80 isolates) expressing a K47 capsular type. Thus, it is significant to prevent and control infections caused by these bacteria. Capsule depolymerases could degrade bacterial surface polysaccharides to reduce their virulence and expose bacteria to host immune attack. Previous studies have demonstrated the potential of phage-encoded depolymerases as antivirulent agents in treating CRKP infections in vitro and in vivo. Here, two capsule depolymerases (Dpo42 and Dpo43) derived from phage IME205 were expressed and characterized. Although both depolymerases act on strains with a capsular serotype K47, they are active against different subsets of strains, indicating subtle differences in capsule composition that exist within this serotype. The host range of phage IME205 matched to the sum of specificity range of Dpo42 and Dpo43. These two enzymes maintained stable activity in a relatively broad range of pH levels (pH 5.0–8.0 for Dpo42 and pH 4.0–8.0 for Dpo43) and temperatures (20–70°C). Besides, both Dpo42 and Dpo43 could make host bacteria fully susceptible to the killing effect of serum complement and display no hemolytic activity to erythrocytes. In summary, capsule depolymerases are promising antivirulent agents to combat CRKP infections.