Gut microbiome predicts cognitive function and depressive symptoms in late life.

Depression in older adults with cognitive impairment increases progression to dementia. Microbiota is associated with current mood and cognition, but the extent to which it predicts future symptoms is unknown. In this work, we identified microbial features that reflect current and predict future cognitive and depressive symptoms. Clinical assessments and stool samples were collected from 268 participants with varying cognitive and depressive symptoms. Seventy participants underwent 2-year follow-up. Microbial community diversity, structure, and composition were assessed using high-resolution 16 S rRNA marker gene sequencing. We implemented linear regression to characterize the relationship between microbiome composition, current cognitive impairment, and depressive symptoms. We leveraged elastic net regression to discover features that reflect current or future cognitive function and depressive symptoms. Greater microbial community diversity associated with lower current cognition in the whole sample, and greater depression in participants not on antidepressants. Poor current cognitive function associated with lower relative abundance of Bifidobacterium, while greater GABA degradation associated with greater current depression severity. Future cognitive decline associated with lower cognitive function, lower relative abundance of Intestinibacter, lower glutamate degradation, and higher baseline histamine synthesis. Future increase in depressive symptoms associated with higher baseline depression and anxiety, lower cognitive function, diabetes, lower relative abundance of Bacteroidota, and lower glutamate degradation. Our results suggest cognitive dysfunction and depression are unique states with an overall biological effect detectable through gut microbiota. The microbiome may present a noninvasive readout and prognostic tool for cognitive and psychiatric states.

[3-O-ß-chacotriosyl glycyrrhetinic acid derivatives as potential small-molecule SARS-CoV-2 fusion inhibitors against SARS-CoV-2 entry into host cells].

OBJECTIVE: To study the inhibitory activities of 3-O-ß-chacotriosyl glycyrrhetinic acid derivatives against the entry of SARS-CoV-2 into host cells. METHODS: With pentacyclic triterpene saponin glycyrrhizic acid (a natural SARS-CoV-2 entry inhibitor) as the lead compound, a series of 3-O-ß-chacotriosyl glycyrrhetinic acid derivatives were designed and synthesized based on hypridization principle, and their inhibitory activities against virus entry were tested in SARS-CoV-2 pseudovirusinfected cells. The antiviral targets of the lead compound 1b was identified by pseudotyped SARS-CoV-2 infection assay and surface plasmon resonance (SPR) assay, and the S protein-mediated cell-cell fusion assay was used to evaluate the effect of 1b on virus-cell membrane fusion. Molecular docking and single amino acid mutagenesis were carried out to analyze the effect of 1b on binding activitiy of S protein. RESULTS: The lead compound 1b showed significant inhibitory effect against Omicron pseudovirus with an EC50 value of 3.28 µmol/L (P < 0.05), and had broad-spectrum antiviral activity against other SARS-CoV-2 pseudovirus. Spike-dependent cell-cell fusion assay demonstrated an inhibitory effect of 1b against SARS-CoV-2 S proteinmediated cell-cell fusion. Molecular docking analysis predicted that the lead compound 1b could be well fitted into a cavity between the attachment (S1) and fusion (S2) subunits at the 3-fold axis, where it formed multiple hydrophobic interactions with Glu309, Ser305, Arg765 and Lys964 residues with a KD value of -8.6 kcal/mol. The compound 1b at 10, 5, 2.5 and 1.25 µmol/L showed a significantly reduced inhibitory activity against the pseudovirus with mutated Arg765, Lys964, Glu309 and Leu303 (P < 0.01). CONCLUSION: 3-O-ß-chacotriosyl glycyrrhetinic acid derivatives are capable of stabilizing spike protein in the pre-fusion step to interfere with the fusion of SARS-CoV-2 with host cell membrane, and can thus serve as potential novel small-molecule SARS-CoV-2 fusion inhibitors.

Worldwide forest surveys reveal forty-three new species in Phytophthora major Clade 2 with fundamental implications for the evolution and biogeography of the genus and global plant biosecurity.

During 25 surveys of global Phytophthora diversity, conducted between 1998 and 2020, 43 new species were detected in natural ecosystems and, occasionally, in nurseries and outplantings in Europe, Southeast and East Asia and the Americas. Based on a multigene phylogeny of nine nuclear and four mitochondrial gene regions they were assigned to five of the six known subclades, 2a-c, e and f, of Phytophthora major Clade 2 and the new subclade 2g. The evolutionary history of the Clade appears to have involved the pre-Gondwanan divergence of three extant subclades, 2c, 2e and 2f, all having disjunct natural distributions on separate continents and comprising species with a soilborne and aquatic lifestyle and, in addition, a few partially aerial species in Clade 2c; and the post-Gondwanan evolution of subclades 2a and 2g in Southeast/East Asia and 2b in South America, respectively, from their common ancestor. Species in Clade 2g are soilborne whereas Clade 2b comprises both soil-inhabiting and aerial species. Clade 2a has evolved further towards an aerial lifestyle comprising only species which are predominantly or partially airborne. Based on high nuclear heterozygosity levels ca. 38 % of the taxa in Clades 2a and 2b could be some form of hybrid, and the hybridity may be favoured by an A1/A2 breeding system and an aerial life style. Circumstantial evidence suggests the now 93 described species and informally designated taxa in Clade 2 result from both allopatric non-adaptive and sympatric adaptive radiations. They represent most morphological and physiological characters, breeding systems, lifestyles and forms of host specialism found across the Phytophthora clades as a whole, demonstrating the strong biological cohesiveness of the genus. The finding of 43 previously unknown species from a single Phytophthora clade highlight a critical lack of information on the scale of the unknown pathogen threats to forests and natural ecosystems, underlining the risk of basing plant biosecurity protocols mainly on lists of named organisms. More surveys in natural ecosystems of yet unsurveyed regions in Africa, Asia, Central and South America are needed to unveil the full diversity of the clade and the factors driving diversity, speciation and adaptation in Phytophthora. Taxonomic novelties: New species: Phytophthora amamensis T. Jung, K. Kageyama, H. Masuya & S. Uematsu, Phytophthora angustata T. Jung, L. Garcia, B. Mendieta-Araica, & Y. Balci, Phytophthora balkanensis I. Milenkovic, Z. Tomic, T. Jung & M. Horta Jung, Phytophthora borneensis T. Jung, A. Durán, M. Tarigan & M. Horta Jung, Phytophthora calidophila T. Jung, Y. Balci, L. Garcia & B. Mendieta-Araica, Phytophthora catenulata T. Jung, T.-T. Chang, N.M. Chi & M. Horta Jung, Phytophthora celeris T. Jung, L. Oliveira, M. Tarigan & I. Milenkovic, Phytophthora curvata T. Jung, A. Hieno, H. Masuya & M. Horta Jung, Phytophthora distorta T. Jung, A. Durán, E. Sanfuentes von Stowasser & M. Horta Jung, Phytophthora excentrica T. Jung, S. Uematsu, K. Kageyama & C.M. Brasier, Phytophthora falcata T. Jung, K. Kageyama, S. Uematsu & M. Horta Jung, Phytophthora fansipanensis T. Jung, N.M. Chi, T. Corcobado & C.M. Brasier, Phytophthora frigidophila T. Jung, Y. Balci, K. Broders & I. Milenkovic, Phytophthora furcata T. Jung, N.M. Chi, I. Milenkovic & M. Horta Jung, Phytophthora inclinata N.M. Chi, T. Jung, M. Horta Jung & I. Milenkovic, Phytophthora indonesiensis T. Jung, M. Tarigan, L. Oliveira & I. Milenkovic, Phytophthora japonensis T. Jung, A. Hieno, H. Masuya & J.F. Webber, Phytophthora limosa T. Corcobado, T. Majek, M. Ferreira & T. Jung, Phytophthora macroglobulosa H.-C. Zeng, H.-H. Ho, F.-C. Zheng & T. Jung, Phytophthora montana T. Jung, Y. Balci, K. Broders & M. Horta Jung, Phytophthora multipapillata T. Jung, M. Tarigan, I. Milenkovic & M. Horta Jung, Phytophthora multiplex T. Jung, Y. Balci, K. Broders & M. Horta Jung, Phytophthora nimia T. Jung, H. Masuya, A. Hieno & C.M. Brasier, Phytophthora oblonga T. Jung, S. Uematsu, K. Kageyama & C.M. Brasier, Phytophthora obovoidea T. Jung, Y. Balci, L. Garcia & B. Mendieta-Araica, Phytophthora obturata T. Jung, N.M. Chi, I. Milenkovic & M. Horta Jung, Phytophthora penetrans T. Jung, Y. Balci, K. Broders & I. Milenkovic, Phytophthora platani T. Jung, A. Pérez-Sierra, S.O. Cacciola & M. Horta Jung, Phytophthora proliferata T. Jung, N.M. Chi, I. Milenkovic & M. Horta Jung, Phytophthora pseudocapensis T. Jung, T.-T. Chang, I. Milenkovic & M. Horta Jung, Phytophthora pseudocitrophthora T. Jung, S.O. Cacciola, J. Bakonyi & M. Horta Jung, Phytophthora pseudofrigida T. Jung, A. Durán, M. Tarigan & M. Horta Jung, Phytophthora pseudoccultans T. Jung, T.-T. Chang, I. Milenkovic & M. Horta Jung, Phytophthora pyriformis T. Jung, Y. Balci, K.D. Boders & M. Horta Jung, Phytophthora sumatera T. Jung, M. Tarigan, M. Junaid & A. Durán, Phytophthora transposita T. Jung, K. Kageyama, C.M. Brasier & H. Masuya, Phytophthora vacuola T. Jung, H. Masuya, K. Kageyama & J.F. Webber, Phytophthora valdiviana T. Jung, E. Sanfuentes von Stowasser, A. Durán & M. Horta Jung, Phytophthora variepedicellata T. Jung, Y. Balci, K. Broders & I. Milenkovic, Phytophthora vietnamensis T. Jung, N.M. Chi, I. Milenkovic & M. Horta Jung, Phytophthora ×australasiatica T. Jung, N.M. Chi, M. Tarigan & M. Horta Jung, Phytophthora ×lusitanica T. Jung, M. Horta Jung, C. Maia & I. Milenkovic, Phytophthora ×taiwanensis T. Jung, T.-T. Chang, H.-S. Fu & M. Horta Jung. Citation: Jung T, Milenkovic I, Balci Y, Janousek J, Kudlácek T, Nagy ZÁ, Baharuddin B, Bakonyi J, Broders KD, Cacciola SO, Chang T-T, Chi NM, Corcobado T, Cravador A, Dordevic B, Durán A, Ferreira M, Fu C-H, Garcia L, Hieno A, Ho H-H, Hong C, Junaid M, Kageyama K, Kuswinanti T, Maia C, Májek T, Masuya H, Magnano di San Lio G, Mendieta-Araica B, Nasri N, Oliveira LSS, Pane A, Pérez-Sierra A, Rosmana A, Sanfuentes von Stowasser E, Scanu B, Singh R, Stanivukovic Z, Tarigan M, Thu PQ, Tomic Z, Tomsovský M, Uematsu S, Webber JF, Zeng H-C, Zheng F-C, Brasier CM, Horta Jung M (2024). Worldwide forest surveys reveal forty-three new species in Phytophthora major Clade 2 with fundamental implications for the evolution and biogeography of the genus and global plant biosecurity. Studies in Mycology 107: 251-388. doi: 10.3114/sim.2024.107.04.

[Pulmonary artery stenting in chronic thromboembolic pulmonary hypertension: a report of 2 cases].

Chronic thromboembolic pulmonary hypertension (CTEPH) is a pulmonary vascular disease characterized by an insidious onset, progressive deterioration, and poor prognosis. It is distinguished by the thrombotic organization within the pulmonary arteries, leading to vascular stenosis or occlusion. This results in a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, ultimately leading to right heart failure. In recent years, balloon pulmonary angioplasty (BPA) has emerged as an effective treatment option for patients ineligible for pulmonary endarterectomy (PEA). However, the use of stents in patients with suboptimal balloon dilation remains controversial. This article describes two cases of chronic thromboembolic pulmonary hypertension (CTEPH) in which balloon angioplasty yielded unsatisfactory results, subsequently leading to stent placement. Following stent implantation, there was improved blood flow, significant reduction in pulmonary arterial pressure, and notable alleviation of patient symptoms. One-year follow-up showed no recurrence of stenosis within the stent, suggesting potential guidance for the use of pulmonary artery stenting as a treatment modality for CTEPH. This report provided new insights into the therapeutic approach for CTEPH.

Discovery of 4,5,6,7-Tetrahydropyrazolo[1.5-a]pyrizine Derivatives as Core Protein Allosteric Modulators (CpAMs) for the Inhibition of Hepatitis B Virus.

Hepatitis B Virus (HBV) core protein allosteric modulators (CpAMs) are an attractive class of potential anti-HBV therapeutic agents. Here we describe the efforts toward the discovery of a series of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (THPP) compounds as HBV CpAMs that effectively inhibit a broad range of nucleos(t)ide-resistant HBV variants. The lead compound 45 demonstrated inhibition of HBV DNA viral load in a HBV AAV mouse model by oral administration.

[A case of metastatic breast cancer complicated by pulmonary tumor thrombotic microangiopathy].

Pulmonary tumor thrombotic microangiopathy is a malignancy-related complication with rapid progression and high mortality. To improve the understanding of the disease, early diagnosis and treatment are key to successful treatment. A 39-year-old patient with pulmonary hypertension transferred from another hospital was admitted to the First Affiliated Hospital of Guangzhou Medical University on September 26, 2021. The patient developed shortness of breath and progressive exacerbation over the past month. No pulmonary artery embolism was seen on computed tomography pulmonary angiography (CTPA) at the outside hospital where the breast cancer was diagnosed. Pulmonary tumor thrombotic microangiopathy was immediately considered on admission and oncological endocrine therapy was started. After treatment, the patient's dyspnoea improved, PET-CT showed significant tumor regression, and cardiac ultrasound showed a significant decrease in pulmonary artery pressure. The successful treatment experience of this case was summarized for reference.

Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection.

Described herein is the first-time disclosure of Linvencorvir (RG7907), a clinical compound and a hepatitis B virus (HBV) core protein allosteric modulator, for the treatment of chronic HBV infection. Built upon the core structure of hetero aryl dihydropyrimidine, RG7907 was rationally designed by combining all the drug-like features of low CYP3A4 induction, potent anti-HBV activity, high metabolic stability, low hERG liability, and favorable animal pharmacokinetic (PK) profiles. In particular, the chemistry strategy to mitigate CYP3A4 induction through introducing a large, rigid, and polar substituent at the position that has less interaction with the therapeutic biological target (HBV core proteins herein) is of general interest to the medicinal chemistry community. RG7907 demonstrated favorable animal PK, pharmacodynamics, and safety profiles with sufficient safety margins supporting its clinical development in healthy volunteers and HBV-infected patients.

Expert consensus on the systemic treatment of atopic dermatitis in special populations.

With the increasing number of options for the treatment of moderate-to-severe atopic dermatitis, clinicians need guidance on a practical approach to selecting a systemic agent for specific patient populations. We convened an expert panel consisting of 12 members to conduct a literature review and summarize relevant data related to six scenarios of clinical interest: comorbid asthma, ocular surface disease, history of cancer, past and ongoing infections of interest (including herpes simplex virus, herpes zoster, hepatitis B, and tuberculosis), pregnancy and lactation, and the elderly. We performed a literature search and examined each clinical scenario with respect to three major categories of available systemic agents: traditional systemics (azathioprine, cyclosporine A, methotrexate, and mycophenolate mofetil), Janus kinase inhibitors (abrocitinib, baricitinib, and upadacitinib), and biologics (dupilumab, lebrikizumab, and tralokinumab). The expert panel and steering committee met virtually to review the data and discuss the drafted consensus statements. A modified Delphi process was used to arrive at a set of final consensus statements related to the systemic treatment of AD in these specific patient populations. To provide practical guidance on the choice of systemic therapy for atopic dermatitis in these six topics of clinical interest, 25 expert consensus statements and a summary of the supporting data are presented herein.

Radiomics signature based on CECT for non-invasive prediction of response to anti-PD-1 therapy in patients with hepatocellular carcinoma.

PURPOSE: This study aimed to develop a radiomics signature (RS) based on contrast-enhanced computed tomography (CECT) and evaluate its potential predictive value in hepatocellular carcinoma (HCC) patients receiving anti-PD-1 therapy. METHOD: CECT scans of 76 HCC patients who received anti-PD-1 therapy were obtained in this study (training group = 53 and validation group = 23). The least absolute shrinkage and selection operator (LASSO) regression was applied to select radiomics features of primary and metastatic lesions and establish a RS to predict lesion-level response. Then, a nomogram combined the mean RS (MRS) and clinical variables with patient-level response as the end point. RESULTS: In the lesion-level analysis, the area under the curves (AUCs) of RS in the training and validation groups were 0.751 (95% CI, 0.668-0.835) and 0.734 (95% CI, 0.604-0.864), respectively. In the patient-level analysis, the AUCs of the nomogram in the training and validation groups were 0.897 (95% CI, 0.798-0.996) and 0.889 (95% CI, 0.748-1.000), respectively. The nomogram stratified patients into low- and high-risk groups, which showed a significant difference in progression-free survival (PFS) (p<0.05). CONCLUSIONS: The RS is a noninvasive biomarker for predicting anti-PD-1 therapy response in patients with HCC. The nomogram may be of clinical use for identifying high-risk patients and formulating individualised treatments.

A New Approach to Quantify and Grade Radiation Dermatitis Using Deep-Learning Segmentation in Skin Photographs.

AIMS: Objective evaluation of radiation dermatitis is important for analysing the correlation between the severity of radiation dermatitis and dose distribution in clinical practice and for reliable reporting in clinical trials. We developed a novel radiation dermatitis segmentation system based on convolutional neural networks (CNNs) to consistently evaluate radiation dermatitis. MATERIALS AND METHODS: The radiation dermatitis segmentation system is designed to segment the radiation dermatitis occurrence area using skin photographs and skin-dose distribution. A CNN architecture with a dilated convolution layer and skip connection was designed to estimate the radiation dermatitis area. Seventy-three skin photographs obtained from patients undergoing radiotherapy were collected for training and testing. The ground truth of radiation dermatitis segmentation is manually delineated from the skin photograph by an experienced radiation oncologist and medical physicist. We converted the skin photographs to RGB (red-green-blue) and CIELAB (lightness (L∗), red-green (a∗) and blue-yellow (b∗)) colour information and trained the network to segment faint and severe radiation dermatitis using three different input combinations: RGB, RGB + CIELAB (RGBLAB) and RGB + CIELAB + skin-dose distribution (RGBLAB_D). The proposed system was evaluated using the Dice similarity coefficient (DSC), sensitivity, specificity and normalised Matthews correlation coefficient (nMCC). A paired t-test was used to compare the results of different segmentation performances. RESULTS: Optimal data composition was observed in the network trained for radiation dermatitis segmentation using skin photographs and skin-dose distribution. The average DSC, sensitivity, specificity and nMCC values of RGBLAB_D were 0.62, 0.61, 0.91 and 0.77, respectively, in faint radiation dermatitis, and 0.69, 0.78, 0.96 and 0.83, respectively, in severe radiation dermatitis. CONCLUSION: Our study showed that CNN-based radiation dermatitis segmentation in skin photographs of patients undergoing radiotherapy can describe radiation dermatitis severity and pattern. Our study could aid in objectifying the radiation dermatitis grading and analysing the reliable correlation between dosimetric factors and the morphology of radiation dermatitis.

A few-shot learning-based eye diseases screening method.

OBJECTIVE: This study aims to construct a brand-new ophthalmic disease screening task and establish a practically valuable ophthalmic disease screening model in the case of insufficient data. MATERIALS AND METHODS: The main methods are as follows: firstly, we mixed data from different sources (these data may come from different cameras, including different fundus diseases) to get a new dataset. Based on this dataset, we conducted subsequent experiments on fundus multi-disease screening. However, in the past public datasets, each dataset often only corresponded to the screening diagnosis of one disease. Secondly, we proposed a method to simulate the characteristics of different fundus cameras by using a method based on style transfer, and to augment the training data, so that the model could learn the features of ophthalmic diseases in a more comprehensive way. Finally, a robust disease screening model based on few-shot learning was constructed on the combined dataset, and compared with benchmark algorithms. RESULTS: We focused on the study of eye disease screening methods based on the metric-based few-shot learning model, data augmentation methods, and focus on key technologies such as data augmentation based on style transfer. Experiments have shown that our method can significantly improve the generalization ability of the disease screening model. CONCLUSIONS: By introducing few-shot learning theory and data augmentation based on style transfer into ophthalmic disease screening, the generalization ability of the model is greatly improved, and it has certain practical value.

[Tuberculosis screening in respiratory department inpatients in comprehensive medical institutions].

Objective: To explore the effect of screening tuberculosis patients in the respiratory department of general hospitals, and to provide a basis for the development of patient screening strategy. Methods: Clinical information and sputum samples of inpatients in the respiratory department of a general hospital in Longhua District, Shenzhen from December 2018 to December 2020 were collected. Sputum samples were sent to the tuberculosis laboratory of the Shenzhen Longhua Center for Chronic Disease Control (designated tuberculosis diagnosis and treatment institution) for sputum smear, liquid culture and Gene-Xpert test. Results: A total of 407 sputum samples (23 cases of suspected tuberculosis by chest imaging and 384 by clinical manifestations) were collected from 3 724 hospitalized patients. A total of 88 patients with positive etiology were detected by the three methods, and the positive rate was 21.6% (88/407), among which 15 patients with suspected tuberculosis were detected by imaging reports, and the positive rate of etiology was 19.0% (73/384) in the reported patients without imaging reports. At least 1.96% (73/3 724) of the hospitalized patients were estimated to be tuberculosis positive during the study. Pneumonia (30.1%,22/73), cough (15.1%,11/73) and pulmonary infection (15.1%,11/73) were the main characteristics in the patients with positive pathogens. Conclusions: Screening for tuberculosis among inpatients in the respiratory department of general hospitals is an effective way to detect patients who were radiographically reported to have probable tuberculosis. It is of great significance to carry out active screening in key departments of general hospitals for tuberculosis detection and control.

Translation Potential and Challenges of In Vitro and Murine Models in Cancer Clinic.

As one of the leading causes of death from disease, cancer continues to pose a serious threat to human health globally. Despite the development of novel therapeutic regimens and drugs, the long-term survival of cancer patients is still very low, especially for those whose diagnosis is not caught early enough. Meanwhile, our understanding of tumorigenesis is still limited. Suitable research models are essential tools for exploring cancer mechanisms and treatments. Herein we review and compare several widely used in vitro and in vivo murine cancer models, including syngeneic tumor models, genetically engineered mouse models (GEMM), cell line-derived xenografts (CDX), patient-derived xenografts (PDX), conditionally reprogrammed (CR) cells, organoids, and MiniPDX. We will summarize the methodology and feasibility of various models in terms of their advantages and limitations in the application prospects for drug discovery and development and precision medicine.

Global trends and regional differences in the burden of anxiety disorders and major depressive disorder attributed to bullying victimisation in 204 countries and territories, 1999-2019: an analysis of the Global Burden of Disease Study.

AIM: This study aimed to analyse the temporal and spatial trends in the burden of anxiety disorders and major depressive disorder related to bullying victimisation on global, regional and country scales. METHODS: Data were from the 2019 Global Burden of Disease (GBD) Study. We assessed the global disability-adjusted life years (DALYs, per 100 000 population) of anxiety disorders and major depressive disorder attributable to bullying victimisation by age, sex and geographical location. The percentage changes in age-standardised rates of DALYs were used to quantify temporal trends, and the annual rate changes across 204 countries and territories were used to present spatial trends. Furthermore, we examined the relationship between the sociodemographic index (SDI) and the burden of anxiety disorders as well as major depressive disorder attributable to bullying victimisation and its spatial and temporal characteristics globally. RESULTS: From 1990 to 2019, the global DALY rates of anxiety disorders and major depressive disorder attributable to bullying victimisation increased by 23.31 and 26.60%, respectively, with 27.27 and 29.07% for females and 18.88 and 23.84% for males. Across the 21 GBD regions, the highest age-standardised rates of bullying victimisation-related DALYs for anxiety disorders were in North Africa and the Middle East and for major depressive disorder in High-income North America. From 1990 to 2019, the region with the largest percentage increase in the rates of DALYs was High-income North America (54.66% for anxiety disorders and 105.88% for major depressive disorder), whereas the region with the slowest growth rate or largest percentage decline was East Asia (1.71% for anxiety disorders and -25.37% for major depressive disorder). In terms of SDI, this study found overall upward trends of bullying-related mental disorders in areas regardless of the SDI levels, although there were temporary downward trends in some stages of certain areas. CONCLUSIONS: The number and rates of DALYs of anxiety disorders and major depressive disorder attributable to bullying victimisation increased from 1990 to 2019. Effective strategies to eliminate bullying victimisation in children and adolescents are needed to reduce the burden of anxiety disorders and major depressive disorder. Considering the large variations in the burden by SDI and geographic location, future protective actions should be developed based on the specific cultural contexts, development status and regional characteristics of each country.

Discovery of Novel cccDNA Reducers toward the Cure of Hepatitis B Virus Infection.

Chronic hepatitis B virus (HBV) infection is a worldwide disease that causes thousands of deaths per year. Currently, there is no therapeutic that can completely cure already infected HBV patients due to the inability of humans to eliminate covalently closed circular DNA (cccDNA), which serves as the template to (re)initiate an infection even after prolonged viral suppression. Through phenotypic screening, we discovered xanthone series hits as novel HBV cccDNA reducers, and subsequent structure optimization led to the identification of a lead compound with improved antiviral activity and pharmacokinetic profiles. A representative compound 59 demonstrated good potency and oral bioavailability with no cellular toxicity. In an HBVcircle mouse model, compound 59 showed excellent efficacy in significantly reducing HBV antigens, DNA, and intrahepatic cccDNA levels.

[Impact of nonsteroidal anti-inflammatory drugs on efficacy of anti-PD-1 therapy for primary liver cancer].

OBJECTIVE: To assess the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on clinical outcomes of patients receiving anti-PD-1 immunotherapy for hepatocellular carcinoma. METHODS: We conducted a retrospective study among 215 patients with primary liver cancer receiving immunotherapy between June, 2018 and October, 2020. The patients with balanced baseline characteristics were selected based on propensity matching scores, and among them 33 patients who used NSAIDs were matched at the ratio of 1∶3 with 78 patients who did not use NSAIDs. We compared the overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) between the two groups. RESULTS: There was no significant difference in OS between the patients using NSAIDs (29.7%) and those who did not use NSAIDs (70.2%). Univariate and multivariate analyses did not show an a correlation of NSAIDs use with DCR (univariate analysis: OR=0.602, 95% CI: 0.299-1.213, P=0.156; multivariate analysis: OR=0.693, 95% CI: 0.330-1.458, P=0.334), PFS (univariate analysis: HR=1.230, 95% CI: 0.789-1.916, P=0.361; multivariate analysis: HR=1.151, 95% CI: 0.732-1.810, P=9.544), or OS (univariate analysis: HR=0.552, 95% CI: 0.208-1.463, P=0.232; multivariate analysis: HR=1.085, 95% CI: 0.685-1.717, P=0.729). CONCLUSION: Our results show no favorable effect of NSAIDs on the efficacy of immunotherapy in patients with advanced primary liver cancer, but this finding still needs to be verified by future prospective studies of large cohorts.

Percutaneous distal clavicle excision for acromioclavicular joint arthritis: our experience and early results of a novel surgical technique.

PURPOSE: Symptomatic acromioclavicular joint (ACJ) osteoarthritis causes pain and limitations in activities of daily living. Open and arthroscopic distal clavicle excision techniques have been described with good outcomes. However, both techniques have their own sets of advantages and disadvantages. This study describes a novel technique of percutaneous distal clavicle excision for symptomatic ACJ osteoarthritis and our two-year results. METHODS: Fifteen consecutive patients underwent percutaneous distal clavicle excision for ACJ arthritis. These patients had failed a trial of conservative treatment. The ACJ was confirmed as the pain generator with an intraarticular steroid/lignocaine injection, and shoulder MRI was used to exclude alternative pain generators in the shoulder. They had a minimum of two years of follow-up. RESULTS: At a mean of 26.8 months postoperatively, the mean VAS pain score was 0, and the mean Constant score for the shoulder was 87.3 points (range 50-94), which corresponded to 1 good, 1 very good and 13 excellent results. The mean SF-36 score was 94.9 points (range 65-100). There were statistically significant improvements in the VAS scores, Constant shoulder scores and SF-36 scores at one year and two years of follow-up (p < 0.05). Three unique complications, namely subcutaneous emphysema, "missing" of the distal clavicle and thermal skin injury, were encountered. Our surgical technique has since been modified to circumvent these complications. CONCLUSION: Our novel technique of percutaneous distal clavicle excision yields a 93.3% good-to-excellent results based on the Constant shoulder score and durable pain relief based on VAS at two years.

An innovation involving self-surveillance and serious gaming to increase smoking quit rate: Protocol for a pilot randomized controlled trial.

Smoking is a health hazard. Current smoking cessation measures such as behavioral change counselling by trained professionals, nicotine replacement therapy and medications have limited success. Smoking intensity is assessed using a portable device to measure the smokers' exhaled breath carbon monoxide (eCO) level. A systematic review suggests the potential of serious gaming to increase smoking quit rate. However, the related studies were unable to explain and determine the effect gamification on smoking cessation. A handy personalized eCO measurement device linked to a smart-phone applications (app) has been developed (integrated STEADES-2 system). This novel system incorporates app-based video and print learning resources, authentication function and gamification using the eCO data as game element. Trained multidisciplinary healthcare professionals access the STEADES-2 data to monitor smoking status and support smokers via asynchronous virtual coaching. The pilot randomized controlled trial will enroll 20 smokers to use the STEADES-2 system (intervention group) and another 20 to the existing smoking cessation programme (control group) in primary care. The primary feasibility outcomes will include the recruitment response rate, the smokers' usability of the STEADES-2 system, their self eCO monitoring, frequencies of participation in the serious games and interactions with their virtual coaches. Their smoking literacy, utility and experience of the STEADES-2 system are other outcomes. Smokers in both groups will be compared on their cigarette abstinence as secondary outcome based on eCO levels and urine cotinine test (primary outcomes after 12 weeks). The results will be disseminated via conferences and publications.

Parental perspectives towards sugar-sweetened beverages and polices: a qualitative study.

PURPOSE: This qualitative study aimed to understand parental perception of (1) sugar-sweetened beverages (SSB) and implications of SSB on health; (2) their role in shaping their children's consumption of SSB; (3) the influences on SSB consumption of their children; and (4) potential government policies targeted at controlling SSB consumption. METHODS: English-speaking parents of pre-schoolers aged 2-6 years were recruited. Semi-structured interviews based on the knowledge, attitude, practice framework were conducted, and transcripts were subjected to thematic analysis based on inductive approaches. Recruitment continued until data saturation was reached. RESULTS: Twenty parents participated in the study and themes addressing the objectives identified. (1) There were misconceptions regarding the healthfulness of certain non-packaged SSB such as traditional remedies and juices. Some were unaware about the association between SSB and dental caries. (2) The need to reduce and restrict sugar consumption for overall and oral health reasons was well-recognised, but the extent of control varied. (3) Multiple stakeholders including pre-schools, grandparents and domestic helpers were involved in shaping children's diet. Children's sugar intake was also influenced by environmental factors, such as the ubiquitously available SSB, targeted marketing and high cost of healthy alternatives. (4) Participants were less accepting towards SSB taxation than the ban of SSB sales. CONCLUSION: Despite the awareness of the types of SSBs and the general/oral health implications of sugar consumption, misconceptions exist. Although most parents possessed the knowledge and attitude, this did not translate into the practice of reducing sugar consumption in their children. There was no SSB reduction policy that had overwhelming acceptability.