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Whei-Lin Pan,1,2 Pi-Lun Chen,2 Cho-Ying Lin,1,2 Yi-Chun Pan,2 Yuh-Ren Ju,1,2 Chiu-Po Chan,1,2 Robert WW Hsu2,3 1Department of Periodontics, Chang Gung Memorial Hospital, Taipei, Taiwan; 2Graduate Institute of Dental and Craniofacial Science, Chang Gung University, Taoyuan, Taiwan; 3Department of Orthopedics, Chang Gung Memorial Hospital, Taipei, Taiwan Abstract: Bisphosphonates (BPs) suppress bone resorption and increase bone strength, thus reducing the risk of fracture. Oral BPs are widely used for the prevention and treatment of osteoporosis and osteopenia. Here, we describe the case of a postmenopausal woman who took oral alendronate for >3 years for osteoporosis. The patient presented at the clinic with sharp jaw pain and swelling on the left mandible 4 months after extraction of the third molar. Clinical examinations identified an inflamed mucosal opening with pus over an area of necrotic bone. Initial images of cone beam computed tomography revealed a sequestrum at the extracted socket. The condition did not improve after 1 week of antibiotic treatment; therefore, the alendronate treatment was terminated and the patient was prescribed strontium ranelate instead. The patient gradually recovered and, at the 2-year follow-up, the site of BP-related osteonecrosis of the jaw healed completely as determined by both clinical and cone beam computed tomography measures. The bone mineral densities in the femoral neck and lumbar spine improved after 1 year, and were maintained at the 3-year follow-up. The serum C-terminal cross-linking telopeptide values also gradually increased from the initial 130 pg/mL to 320 pg/mL at the 3-year follow-up. Taken together, this case supports the use of strontium ranelate as an alternative treatment for postmenopausal women who receive long-term oral BP treatments and are at risk for serious complications of BP-related osteonecrosis of the jaw. Keywords: bisphosphonate-related osteonecrosis of the jaw, BRONJ, bisphosphonates, strontium ranelate

We introduce a topology-aware performance optimization and modeling workflow for AMR simulation that includes two new modeling tools, ProgrAMR and Mota Mapper, which interface with the BoxLib AMR framework and the SSTmacro network simulator. ProgrAMR allows us to generate and model the execution of task dependency graphs from high-level specifications of AMR-based applications, which we demonstrate by analyzing two example AMR-based multigrid solvers with varying degrees of asynchrony. Mota Mapper generates multiobjective, network topology-aware box mappings, which we apply to optimize the data layout for the example multigrid solvers. While the sensitivity of these solvers to layout and execution strategy appears to be modest for balanced scenarios, the impact of better mapping algorithms can be significant when performance is highly constrained by network hop latency. Furthermore, we show that network latency in the multigrid bottom solve is the main contributing factor preventing good scaling on exascale-class machines.

OBJECTIVE: Transforming growth factor [beta]1 (TGF-[beta]1) plays a role in repair and dentinogenesis in dental pulp. The purpose of this study was to study how TGF-[beta]1 affects 2 differentiation markers, Runt-related transcription factor 2 (Runx-2) and ALP, in dental pulp cells. STUDY DESIGN: Primary-cultured human dental pulp cells were treated with TGF-[beta]1 with or without pretreatment and coincubation with 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene (U0126, a mitogen-induced extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor), Noggin (a bone morphogenetic protein inhibitor), or 4-(5-benzol[1,3]dioxol-5-yl-4-pyrldin-2-yl-1H-imidazol-2-yl)-be nzamide hydrate (SB431542, an activin receptor-like kinase (ALK) 5/Smad2/3 inhibitor). The differentiation status of pulp cells was evaluated by ALP staining and quantitative ALP activity assay. Changes in ALP and Runx-2 mRNA expression were determined by reverse-transcription polymerase chain reaction. RESULTS: Cells under the treatment of TGF-[beta]1 (5 and 10 ng/mL) showed a decrease in ALP activity and gene expression of ALP and Runx-2. Pretreatment by U0126 and Noggin was not effective to prevent the TGF-[beta]1-induced decline of ALP activity. Interestingly, SB431542 prevented the TGF-[beta]1-induced decline of ALP activity and ALP and Runx-2 gene expression. CONCLUSION: TGF-[beta]1 down-regulates Runx-2 and ALP in human dental pulp cells via ALK5/Smad2/3 signaling. These events may play important roles at specific stages of pulpal repair and dentinogenesis. [ABSTRACT FROM AUTHOR]

Background: Protease-activated receptors (PARs) can be stimulated by thrombin and other proteases generated by periodontal pathogens. Activation of PARs in gingival fibroblasts (GFs) can modulate wound healing and inflammatory responses in gingival tissues.Methods: The mRNA expression of PARs and early responsive genes in GFs and other oral cells was studied by reverse transcription-polymerase chain reaction. Western blotting was used to study the activation of p38 and cAMP responsive element binding protein (CREB)/activating transcription factor (ATF)-1 as well as Ras.Results: GFs, dental pulp cells, and buccal mucosal fibroblasts expressed PAR-1 and -3 receptors, whereas gingival keratinocytes expressed PAR-1 and -2 receptors. Stimulation of GFs by thrombin rapidly activated Ras signaling and the phosphorylation of CREB/ATF-1 and p38. Thrombin also stimulated the expression of c-fos in GFs within 1 hour of exposure. Stimulation of c-jun mRNA expression showed biphasic responses with two peaks after 1 and 8 hours of exposure. Elevated c-myc expression in GFs by thrombin was noted after 2 hours of exposure. Moreover, the stimulation of c-fos and c-myc mRNA expression by thrombin can be attenuated by D-Phe-Pro-ArgCH(2)Cl, a serine-proteinase inhibitor.Conclusions: PAR activation during gingival wounding or inflammation may stimulate Ras-CREB/ATF-1 signaling and c-fos, c-jun, and c-myc expression. This might be due to the proteinase activity of thrombin. These signaling events are important for wound healing and inflammatory responses in gingival tissues. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure and a non-left bundle branch block (non-LBBB) QRS pattern have a limited response to biventricular pacing (BVP)., Objective: A personalized cardiac resynchronization therapy (CRT) implantation approach guided by real-time electrocardiographic imaging (ECGi) was studied., Methods: Twenty patients with left ventricular ejection fraction (LVEF) ≤ 35%, QRS duration ≥ 120 ms, and non-LBBB [13 (65%) with right bundle branch block and 7 (35%) with intraventricular conduction delay] were recruited. During CRT implantation, right atrial, right ventricular, coronary sinus, His-bundle, and/or left bundle leads were inserted. The total activation time (TAT) with different pacing combinations were measured in real time during implantation by ECGi. The configuration producing the shortest TAT was chosen. Clinical response was defined as ≥1 New York Heart Association class improvement. Echocardiographic response was defined as left ventricular end-systolic volume reduction ≥ 15% and/or LVEF improvement ≥ 10% at 6 months., Results: After ECGi-guided CRT implantation, LVEF improved from 26% ± 6% to 34% ± 11% (P < .01) and New York Heart Association class improved from 3.0 ± 0.5 to 2.0 ± 0.6 (P < .01). Both clinical and echocardiographic response rates were 70%. The ECGi approach resulted in better acute electrical resynchronization over BVP as measured by TAT reduction (40% vs 14%; P < .01). The percentage of TAT reduction was found to be a strong predictor for echocardiographic response (area under the curve for the receiver operating characteristic curve 0.91; 95% confidence interval 0.78-1.00). A strong positive correlation between percentage TAT reduction and percentage LVEF improvement (Pearson R = 0.70; P = .001) was found., Conclusion: ECGi-guided CRT implantation in patients with non-LBBB generates superior acute electrical resynchronization compared with BVP and is associated with favorable clinical and echocardiographic outcomes., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Exposure risk was shown to have affected individual susceptibility and the epidemic spread of COVID-19. The dynamics of risk by and across exposure settings alongside the variations following the implementation of social distancing interventions are understudied., Objective: This study aims to examine the population's trajectory of exposure risk in different settings and its association with SARS-CoV-2 infection across 3 consecutive Omicron epidemic waves in Hong Kong., Methods: From March to June 2022, invitation letters were posted to 41,132 randomly selected residential addresses for the recruitment of households into a prospective population cohort. Through web-based monthly surveys coupled with email reminders, a representative from each enrolled household self-reported incidents of SARS-CoV-2 infections, COVID-19 vaccination uptake, their activity pattern in the workplace, and daily and social settings in the preceding month. As a proxy of their exposure risk, the reported activity trend in each setting was differentiated into trajectories based on latent class growth analyses. The associations of different trajectories of SARS-CoV-2 infection overall and by Omicron wave (wave 1: February-April; wave 2: May-September; wave 3: October-December) in 2022 were evaluated by using Cox proportional hazards models and Kaplan-Meier analysis., Results: In total, 33,501 monthly responses in the observation period of February-December 2022 were collected from 5321 individuals, with 41.7% (2221/5321) being male and a median age of 46 (IQR 34-57) years. Against an expanding COVID-19 vaccination coverage from 81.9% to 95.9% for 2 doses and 20% to 77.7% for 3 doses, the cumulative incidence of SARS-CoV-2 infection escalated from <0.2% to 25.3%, 32.4%, and 43.8% by the end of waves 1, 2, and 3, respectively. Throughout February-December 2022, 52.2% (647/1240) of participants had worked regularly on-site, 28.7% (356/1240) worked remotely, and 19.1% (237/1240) showed an assorted pattern. For daily and social settings, 4 and 5 trajectories were identified, respectively, with 11.5% (142/1240) and 14.6% (181/1240) of the participants gauged to have a high exposure risk. Compared to remote working, working regularly on-site (adjusted hazard ratio [aHR] 1.47, 95% CI 1.19-1.80) and living in a larger household (aHR 1.12, 95% CI 1.06-1.18) were associated with a higher risk of SARS-CoV-2 infection in wave 1. Those from the highest daily exposure risk trajectory (aHR 1.46, 95% CI 1.07-2.00) and the second highest social exposure risk trajectory (aHR 1.52, 95% CI 1.18-1.97) were also at an increased risk of infection in waves 2 and 3, respectively, relative to the lowest risk trajectory., Conclusions: In an infection-naive population, SARS-CoV-2 transmission was predominantly initiated at the workplace, accelerated in the household, and perpetuated in the daily and social environments, as stringent restrictions were scaled down. These patterns highlight the phasic shift of exposure settings, which is important for informing the effective calibration of targeted social distancing measures as an alternative to lockdown., (©Chin Pok Chan, Shui Shan Lee, Tsz Ho Kwan, Samuel Yeung Shan Wong, Eng-Kiong Yeoh, Ngai Sze Wong. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 19.06.2024.)

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; I 2  = 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., (© 2024. The Author(s).)

Aims: Aveir VR performance and predictors for its pacing threshold (PCT) in a real-world cohort were investigated., Methods: Electrical measurements at various stages of an Aveir VR implant were prospectively collected. Predictors for 3-month PCT were studied. A retrospective cohort of consecutive 139 Micra implants was used to compare the PCT evolution. High PCT was defined as ≥1.5 V, using a pulse width of 0.4 ms for Aveir and 0.24 ms for Micra. Excellent PCT was defined as ≤0.5 V at the respective pulse width., Results: Among the 123 consecutive Aveir VR implant attempts, 122 (99.2%) were successful. The majority were of advanced age (mean 79.7) and small body size (mean BSA 1.60). Two patients (1.6%) experienced complications, including one pericardial effusion after device reposition and one intraoperative device dislodgement. Eighty-eight patients reached a 3-month follow-up. Aveir 3-month PCT was correlated with impedance at mapping (P = 0.015), tether mode (P < 0.001), end-of-procedure (P < 0.001), and mapping PCT (P = 0.035), but not with PCTs after fixation (P > 0.05). Tether mode impedance >470 ohms had 88% sensitivity and 71% specificity in predicting excellent 3-month PCT. Although it is more common for Aveir to have high PCT at end of procedure (11.5% for Aveir and 2.2% for Micra, P = 0.004), the rate at 3 months was similar (2.3% for Aveir and 3.1% for Micra, P = 1.000)., Conclusion: Aveir VR demonstrated satisfactory performance in this high-risk cohort. Pacing thresholds tend to improve to a greater extent than Micra after implantation. The PCT after fixation, even after a waiting period, has limited predictive value for the chronic threshold. Low-mapping PCT and high intraoperative impedance predict chronic low PCT., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Members of the serine-arginine protein kinase (SRPK) family, SRPK1 and SRPK2, phosphorylate the hepatitis B core protein (Cp) and are crucial for pregenomic RNA encapsidation during viral nucleocapsid assembly. Among them, SRPK2 exhibits higher kinase activity toward Cp. In this study, we identified Cp sites that are phosphorylated by SRPK2 and demonstrated that the kinase utilizes an SRPK-specific docking groove to interact with and regulate the phosphorylation of the C-terminal arginine rich domain of Cp. We determined that direct interaction between the docking groove of SRPK2 and unphosphorylated Cp inhibited premature viral capsid assembly in vitro, whereas the phosphorylation of the viral protein reactivated the process. Pull-down assays together with the new cryo-electron microscopy structure of the HBV capsid in complex with SRPK2 revealed that the kinases decorate the surface of the viral capsid by interacting with the C-terminal domain of Cp, underscoring the importance of the docking interaction in regulating capsid assembly and pregenome packaging. Moreover, SRPK2-knockout in HepG2 cells suppressed Cp phosphorylation, indicating that SRPK2 is an important cellular kinase for HBV life cycle., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Integrative Chinese and Western medicine (ICWM) is commonly used for the treatment of ulcerative colitis (UC) in clinical practice. However, it is unclear whether the details of ICWM interventions, such as selection rationale, implementation design, and potential interactions, were adequately reported. Therefore, this study aimed to assess the quality of reporting in the ICWM interventional randomized controlled trials (RCTs) of UC and to identify the common problems if any., Methods: Through a search of 10 international electronic databases, we identified RCTs of UC with ICWM interventions published in English or Chinese from the inception date of each database up to 16 June 2023. Literature screening was strictly conducted based on the inclusion and exclusion criteria of the Population, Concept, and Context (PCC) framework. The general characteristics of the included studies were described. The quality of reporting was assessed according to three checklists, including the CONSORT (Consolidated Standards of Reporting Trials) with 36 items (except for one item 1b about abstract), the CONSORT for Abstracts (17 items), and a self-designed ICWM-related checklist (27 items covering design rationale, intervention details, outcome assessments, and analysis). The reporting scores of RCTs published before and after 2010 were compared., Results: A total of 1458 eligible RCTs were included. For the reporting compliance, the median score (interquartile ranges) of the CONSORT (72 score in total), the CONSORT for Abstract (34 score), and ICWM-related (54 score) items was 21 (18-25), 13 (12-15), and 18 (15-21), respectively. Although the time period comparisons showed that reporting quality of included publications improved significantly after the CONSORT 2010 issued (P < 0.01), more than 50% of items were evaluated as poor quality (reporting rate < 65%) among each checklist, especially in the CONSORT for Abstract and ICWM-specific items., Conclusion: Although CONSORT appears to have enhanced the reporting of RCTs in UC, the quality of ICWM specifics is variable and in need of improvement. Reporting guidelines of the ICWM recommendations should be developed to improve their quality., (© 2023. The Author(s).)

Background: During slow pathway modification for atrioventricular nodal reentrant tachycardia, heart block may occur if ablation cannot be stopped in time in response to high risk electrogram features (HREF)., Objectives: To develop an automatic algorithm to monitor HREF and terminate ablation earlier than human reaction., Methods: Digital electrogram data from 332 ablation runs from February 2020 to June 2022 were included. They were divided into training and validation sets which contained 126 and 206 ablation runs respectively. HREF in training set was measured. Then a program was developed with cutoff values decided from training set to capture all these HREF. Simulation ablation videos were rendered using validation set electrogram data. The videos were played to three independent electrophysiologists who each determined when to stop ablation. Timing of ablation termination, sensitivity, and specificity were compared between human and program., Results: Reasons for ablation termination in the training set include short AA time, short VV time, AV block and VA block. Cutoffs for the program were set to maximize program sensitivity. Sensitivity and specificity for the program in the validation set were 95.2% and 91.1% respectively, which were comparable to that of human performance at 93.5% and 95.4%. If HREF were recognized by both human and program, ablations were terminated earlier by the program 90.2% of times, by a median of 574 ms (interquartile range 412-807 ms, p  < 0.001)., Conclusion: Algorithmic-driven monitoring of slow pathway modification can supplement human judgement to improve ablation safety., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Tam, Lai, Chan, Au, Chan, Cheng and Yan.)

With "undetectable equals untransmittable," continued engagement in condomless sex has prolonged STI risk in people living with HIV. This study examined the pattern and relationship between STI diagnosis and sex partner-seeking practice over time in a cohort of men who have sex with men (MSM) attending the HIV specialist clinic in Hong Kong. Participants' STI diagnosis record since HIV diagnosis was retrieved and their frequency of seeking sex partners (A) before, (B) after HIV diagnosis, and (C) following extended period (5-10 years), through eight different settings, was assessed in two rounds of survey, along with their risk behavioral profile. Multivariable regression models were employed to study the factors associated with STI diagnosis and partner-seeking frequency, while their temporal relationships over the three time points (A-C) were examined using cross-lagged panel model. Of 345 subjects recruited, STI incidence dropped from 252 to 187 cases/1000 person-years during 2015-2019. Totally 139/212 MSM (66%) had ≥ 1 episode of STI within the 10-year period after HIV diagnosis, giving an 11-20% annual prevalence. The reduced frequency of seeking sex partner was well preserved following diagnosis with a rebound specifically noted in the use of mobile application, the patrons of which were more likely to be co-infected with STI in 2019. Chemsex, concurrent partnership, and casual sex were risk factors shared between frequent partner-seeking practice and STI diagnosis. A robust autoregressive effect for partner-seeking frequency was also identified, and which significantly predicted STI risk in the long term. To enhance HIV care, the co-administration of STI/behavioral surveillance should be emphasized., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cholesterol plays a vital role in multiple physiological processes. Cellular uptake of cholesterol is mediated primarily through endocytosis of low-density lipoprotein (LDL) receptor. New modifiers of this process remain to be characterized. Particularly, the role of fasting- and CREB-H-induced (FACI) protein in cholesterol homeostasis merits further investigation., Methods: Interactome profiling by proximity labeling and affinity purification - mass spectrometry was performed. Total internal reflection fluorescence microscopy and confocal immunofluorescence microscopy were used to analyze protein co-localization and interaction. Mutational analysis was carried out to define the domain and residues required for FACI localization and function. Endocytosis was traced by fluorescent cargos. LDL uptake in cultured cells and diet-induced hypercholesterolemia in mice were assessed., Results: FACI interacted with proteins critically involved in clathrin-mediated endocytosis, vesicle trafficking, and membrane cytoskeleton. FACI localized to clathrin-coated pits (CCP) on plasma membranes. FACI contains a conserved DxxxLI motif, which mediates its binding with the adaptor protein 2 (AP2) complex. Disruption of this motif of FACI abolished its CCP localization but didn't affect its association with plasma membrane. Cholesterol was found to facilitate FACI transport from plasma membrane to endocytic recycling compartment in a clathrin- and cytoskeleton-dependent manner. LDL endocytosis was enhanced in FACI-overexpressed AML12 cells but impaired in FACI-depleted HeLa cells. In vivo study indicated that hepatic FACI overexpression alleviated diet-induced hypercholesterolemia in mice., Conclusions: FACI facilitates LDL endocytosis through its interaction with the AP2 complex., (© 2023. The Author(s).)

Single-cycle infectious virus can elicit close-to-natural immune response and memory. One approach to generate single-cycle severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is through deletion of structural genes such as spike (S) and nucleocapsid (N). Transcomplementation of the resulting ΔS or ΔN virus through enforced expression of S or N protein in the cells gives rise to a live but unproductive virus. In this study, ΔS and ΔN BAC clones were constructed and their live virions were rescued by transient expression of S and N proteins from the ancestral and the Omicron strains. ΔS and ΔN virions were visualized by transmission electron microscopy. Virion production of ΔS was more efficient than that of ΔN. The coated S protein from ΔS was delivered to infected cells in which the expression of N protein was also robust. In contrast, expression of neither S nor N was detected in ΔN-infected cells. ΔS underwent viral RNA replication, induced type I interferon (IFN) response, but did not form plaques. Despite RNA replication in cells, ΔS infection did not produce viral progeny in culture supernatant. Interestingly, viral RNA replication was not further enhanced upon overexpression of S protein. Taken together, our work provides a versatile platform for development of single-cycle vaccines for SARS-CoV-2., (© 2022 Wiley Periodicals LLC.)

Background: The COVID-19 Omicron BA.2 epidemic wave in Hong Kong peaked in the first quarter of 2022. Following the implementation of stringent public health measures, the daily number of reported cases fell from over 50,000 to below 2000. Although outbreaks steadily receded, the government rolled out a 3-day "voluntary universal rapid testing" campaign to invite all citizens to self-perform a rapid antigen test (RAT) daily to identify undetected prevalent infections., Objective: This study aimed to evaluate the uptake and results of RAT mass screening to estimate the population's residual epidemic burden and assess the risk of further transmission., Methods: A cross-sectional study comprising an open web-based population-based survey was conducted a week after the RAT campaign. Participants were asked to report their COVID-19 vaccination and infection history and the RAT performance and test result during the period. They were also invited to report their coliving individuals' test performance and results. Reasons for nonuptake were enquired. Testing and positive rates were age-adjusted. Determinants of undergoing RAT were identified using univariable and multivariable logistic regression models., Results: In total, particulars from 21,769 individuals were reported by 8338 participants. The overall age-adjusted testing rate was 74.94% (95% CI 73.71%-76.18%), with over 80% of participants in the age groups between 45-84 years having self-performed RAT during the campaign period. After age-adjustment, 1.03% (95% CI 0.86%-1.21%) of participants tested positive. The positive rates in the age groups between 20-29 years and >84 years exceeded 2%. Taking into account the positive rate and 5819 reported cases during the period, the cases identified in the campaign might account for 7.65% (95% CI 6.47%-9.14%) of all infections. Testers were more likely to be female, older, not previously diagnosed with COVID-19, and have received COVID-19 vaccination. Adjusting for the number of household members, those living with a child aged <12 years and whose household members were also tested were more likely to have self-performed an RAT. Main reasons for not performing an RAT included the absence of symptoms (598/1108, 53.97%), disbelief of the appropriateness of the campaign as an antiepidemic measure (355/1108, 32.04%), and a recent COVID-19 diagnosis (332/1108, 29.96%)., Conclusions: The residual population burden remained substantial in spite of the clear evidence of a receding epidemic wave. Despite caution in generalization to the Hong Kong population, the high participation rate in mass screening indicated that the voluntary RAT was well accepted, making it a feasible option for implementation as a complementary means of public health surveillance., (©Tsz Ho Kwan, Ngai Sze Wong, Chin Pok Chan, Eng Kiong Yeoh, Samuel Yeung-shan Wong, Shui Shan Lee. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 09.11.2022.)

Background: Worldwide, the COVID-19 pandemic has disrupted influenza seasonality and impacted influenza vaccination behaviours. This study examines the patterns of influenza vaccination uptake in nurses during the pre-pandemic seasons and amidst the pandemic in 2020/21 in subtropical Hong Kong., Methods: In April 2021, a cross-sectional survey was conducted in practising and student nurses. Six patterns were differentiated by their influenza vaccination status in 2020/21 and preceding five seasons: (a) resistance throughout, (b) negative change, (c) decreased tendency, (d) increased tendency (e) positive change, and (f) adherence throughout. Participants' characteristics and reasons for vaccination/non-vaccination and their associations with each vaccination pattern were explored using multivariable multinomial regression., Results: Among 1323 nurses (88% female with a median age of 39 years), no substantial change in vaccination uptake was noted from 2019/20 (41%) to 2020/21 (42%). Some 4% were positive-changers who were older at age of ≥50 years (aOR 4.77) and more likely to anticipate a reduced risk of severe disease with COVID-19/influenza co-infection following vaccination (aOR 8.76). Negative-changers made up 3% and were more inclined to perceive an unlikelihood of widespread influenza outbreaks amidst the pandemic (aOR 3.67). Some 26 and 43% remained adherent and resistant to influenza vaccination throughout respectively notwithstanding the COVID-19 outbreak., Conclusions: In contrast to the increased uptake elsewhere, the stable influenza vaccination coverage among nurses in Hong Kong could be explained by the ubiquity of strict physical distancing regulations, which have deterred vaccination in some nurses that offsets the new uptakes induced by the mild COVID-19 outbreaks.

Background: During the early phase of the Coronavirus Disease 2019 (COVID-19) epidemic, health care workers had elevated levels of psychological distress. Historical exposure to disease outbreak may shape different pandemic responses among experienced health care workers., Aim: Considering the unique experience of the 2003 SARS outbreak in Hong Kong, this study examined the association between prior epidemic work experience and anxiety levels, and the mediating role of perceived severity of COVID-19 and SARS in nurses., Methods: In March 2020, a cross-sectional survey targeting practising nurses in Hong Kong was conducted during the early phase of the COVID-19 epidemic. The interrelationships among participants' work experience during the SARS outbreak, perceived severity of SARS and COVID-19, and anxiety level were elucidated using structural equation model (SEM)., Findings: Of 1,061 eligible nurses, a majority were female (90%) with a median age of 39 years (IQR = 32-49). A significant and negative indirect association was identified between SARS experience and anxiety levels (B=-0.04, p=0.04) in the SEM with a satisfactory fitness (CFI=0.95; RMSEA=0.06). SARS-experienced nurses perceived SARS to be less severe (B=-0.17, p=0.01), translated an equivalent perception to COVID-19 (B=1.29, p<0.001) and resulted in a lower level of anxiety (B=0.19, p<0.001)., Conclusions: The less vigorous perception towards the severity of SARS and COVID-19 may explain SARS-experienced nurses' less initial epidemic-induced anxiety. The possible role of outbreak-experienced nurses in supporting outbreak-inexperienced nurses, both emotionally and technically, should be considered when an epidemic commences. Interventions aiming to facilitate the understanding of emerging virus should also be in place., (© 2022 Australian College of Nursing Ltd. Published by Elsevier Ltd.)

Background and Objectives: This single-center study aimed to assess the role of laparoscopic greater curvature plication (LGCP) in bariatric surgery. Materials and Methods: Using data from our institution’s prospectively maintained database, we identified adult patients with obesity who underwent either laparoscopic sleeve gastrectomy (LSG) or LGCP between January 2012 and July 2017. In total, 280 patients were enrolled in this study. Results: The body mass index was higher in the LSG group than in the LGCP group (39.3 vs. 33.3, p < 0.001). Both groups achieved significant weight loss during the 3-year follow-up (p < 0.001). The weight-reduction rate was higher in the LSG group than in the LGCP group 6, 12, and 24 months postoperatively (p = 0.001, 0.001, and 0.012, respectively). The reoperation rate of the LGCP group was higher than that of the LSG group (p = 0.001). No deaths were recorded in either group. Conclusions: Although both the LGCP and LSG groups achieved significant weight loss over three years, the LGCP group demonstrated a lower weight-reduction rate and a higher reoperation rate than the LSG group. Thus, it is necessary to reassess the role of LGCP in bariatric surgery, particularly when LSG is a feasible alternative.

Objectives: People who inject drugs (PWID) constitute a population group with a high hepatitis C virus (HCV) burden. With the objectives of assessing the HCV prevalence in PWID and determining the proportion requiring treatment who could be linked to care, this study piloted onsite reflex HCV testing at low threshold methadone clinics, with prompt referral of HCV RNA-positive participants for treatment., Methods: This was a prospective study on methadone clinic attendees in Hong Kong. Questionnaires were completed, finger-prick anti-HCV rapid testing was performed, and positive blood samples were collected for laboratory HCV RNA testing. The proportions of participants along the cascade of HCV care were calculated., Results: In 2021-2022, after 14 evening screening sessions at three methadone clinics, 86 of 354 regular attendees (24%) were recruited. The anti-HCV prevalence was 63% (54/86, 95% confidence interval 52-73%), with 78% (42/54) testing positive for HCV RNA and 79% (33/42) successfully referred. Almost all (31/33) referred participants received direct-acting antiviral (DAA) treatment, 94% (29/31) with full treatment compliance; 55% (16/29) of these compliant participants achieved a sustained virological response, while the remainder had not received post-treatment testing., Conclusions: The use of a simplified testing algorithm in the setting of substitution treatment services, incorporating reflex HCV testing, could be an effective strategy for contributing towards the micro-elimination of HCV in PWID., (© 2022 The Author(s).)

Background: Expression of genes of interest from plasmids or lentiviral vectors is one of the most common tools in molecular and gene therapy. Aberrant splicing between the inserted gene of interest and downstream vector sequence has not been systematically analyzed. Methods: Formation of aberrant fusion transcripts and proteins was detected by RT-PCR, sequencing, Western blotting and mass spectrometry. Bioinformatic analysis was performed to identify all human and mouse genes prone to vector-dependent aberrant splicing. Selected genes were experimentally validated. Results: When we expressed human FACI in cultured cells, an aberrant splicing event was found to occur between FACI transcript and downstream plasmid sequence through one exon-exon junction in FACI that accidentally contributes a splice donor site. To explore whether this could be a general phenomenon, we searched the whole human and mouse genomes for protein-coding genes that harbor an exon-exon junction resembling a splice donor site. Almost all genes prone to this type of aberrant splicing were identified. A total of 17 genes among the hits were randomly selected for experimental validation. RT-PCR and sequencing results verified that 13 genes were aberrantly spliced on the identified exon-exon junctions. In addition, all 17 genes were aberrantly spliced on their V5 tag sequence. Aberrant fusion protein expression from all 17 genes was validated by immunoblotting. Aberrant splicing was prevented by recoding the V5 tag or the splice sites. Conclusions: Our study revealed an unexpectedly high frequency of vector-dependent aberrant splicing events. Aberrant formation of the resulting fusion proteins could undermine the accuracy of gain-of-function studies and might cause potential side effects when the therapeutic gene is expressed in vivo . Our work has implications in improving vector construction and epitope tagging for gene expression and therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Human immunodeficiency virus (HIV) functional cure is a novel biomedical strategy characterized by sustained viral suppression without the need for life-long medications. The attitude of people living with HIV (PLHIV) towards functional cure and clinical trials are understudied. We aimed to examine the awareness and levels of anticipation for HIV functional cure among men who have sex with men (MSM) living with HIV, and their willingness to join trials as differentiated by their antiretroviral treatment status., Methods: MSM living with HIV with and those without treatment history were recruited from Hong Kong's HIV specialist clinics. Self-administered questionnaires covering behavioral profile, perceived impact of HIV cure, attitude towards HIV functional cure and related clinical trials were collected. Clinical data were separately transcribed. Determinants of perceptions and attitudes were identified by logistic regression models., Results: Of 356 MSM living with HIV recruited, less than half (42%) were aware of HIV functional cure, but they had a high level of anticipation for it. Treatment-experienced participants were more likely to be aware of HIV functional cure. Awareness was associated with continued engagement in sexual activities after HIV diagnosis and sexually transmitted infection (STI) diagnosis. Higher anticipation was observed among older MSM living with HIV but it was negatively associated with one's awareness. Over 90% were willing to join functional cure trials, especially those who had previously been diagnosed with STI and had engaged in chemsex in the past year. Advice from healthcare professional was an important factor considered by those willing to join clinical trials. Younger, better educated MSM, and those with lower CD4 counts were more concerned about potential risk of AIDS and potential complications upon trial participation., Conclusions: MSM living with HIV, especially those sexually active, showed positive attitude towards functional cure and willingness to join related clinical trials despite low awareness. To enhance preparedness for HIV functional cure trials, community education, updated information and appropriate medical advice would be needed. Safety is a major concern for potential enrollees in HIV functional cure trials., (© 2022. The Author(s).)

Sensing of pathogen-associated molecular patterns including viral RNA by innate immunity represents the first line of defense against viral infection. In addition to RIG-I-like receptors and NOD-like receptors, several other RNA sensors are known to mediate innate antiviral response in the cytoplasm. Double-stranded RNA-binding protein PACT interacts with prototypic RNA sensor RIG-I to facilitate its recognition of viral RNA and induction of host interferon response, but variations of this theme are seen when the functions of RNA sensors are modulated by other RNA-binding proteins to impinge on antiviral defense, proinflammatory cytokine production and cell death programs. Their discrete and coordinated actions are crucial to protect the host from infection. In this review, we will focus on cytoplasmic RNA sensors with an emphasis on their interplay with RNA-binding partners. Classical sensors such as RIG-I will be briefly reviewed. More attention will be brought to new insights on how RNA-binding partners of RNA sensors modulate innate RNA sensing and how viruses perturb the functions of RNA-binding partners., (© 2022 Chan and Jin; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Background: SARS-CoV-2 is the causative agent of COVID-19. Overproduction and release of proinflammatory cytokines are the underlying cause of severe COVID-19. Treatment of this condition with JAK inhibitors is a double-edged sword, which might result in the suppression of proinflammatory cytokine storm and the concurrent enhancement of viral infection, since JAK signaling is essential for host antiviral response. Improving the current JAK inhibitor therapy requires a detailed molecular analysis on how SARS-CoV-2 modulates interferon (IFN)-induced activation of JAK-STAT signaling., Results: In this study, we focused on the molecular mechanism by which SARS-CoV-2 NSP13 helicase suppresses IFN signaling. Expression of SARS-CoV-2 NSP13 alleviated transcriptional activity driven by type I and type II IFN-responsive enhancer elements. It also prevented nuclear translocation of STAT1 and STAT2. The suppression of NSP13 on IFN signaling occurred at the step of STAT1 phosphorylation. Nucleic acid binding-defective mutant K345A K347A and NTPase-deficient mutant E375A of NSP13 were found to have largely lost the ability to suppress IFN-β-induced STAT1 phosphorylation and transcriptional activation, indicating the requirement of the helicase activity for NSP13-mediated inhibition of STAT1 phosphorylation. NSP13 did not interact with JAK1 nor prevent STAT1-JAK1 complex formation. Mechanistically, NSP13 interacted with STAT1 to prevent JAK1 kinase from phosphorylating STAT1., Conclusion: SARS-CoV-2 NSP13 helicase broadly suppresses IFN signaling by targeting JAK1 phosphorylation of STAT1., (© 2022. The Author(s).)

Background & Aims: CREB-H is a key liver-enriched transcription factor governing lipid metabolism. Additional targets of CREB-H remain to be identified and characterized. Here, we identified a novel fasting- and CREB-H-induced (FACI) protein that inhibits intestinal lipid absorption and alleviates diet-induced obesity in mice., Methods: FACI was identified by reanalysis of existing transcriptomic data. Faci -/- mice were generated by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9)-mediated genome engineering. RNA sequencing was performed to identify differentially expressed genes in Faci -/- mice. Lipid accumulation in the villi was assessed by triglyceride measurement and Oil red O staining. In vitro fatty acid uptake assay was performed to verify in vivo findings., Results: FACI expression was enriched in liver and intestine. FACI is a phospholipid-binding protein that localizes to plasma membrane and recycling endosomes. Hepatic transcription of Faci was regulated by not only CREB-H, but also nutrient-responsive transcription factors sterol regulatory element-binding protein 1 (SREBP1), hepatocyte nuclear factor 4α (HNF4α), peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α), and CREB, as well as fasting-related cyclic adenosine monophosphate (cAMP) signaling. Genetic knockout of Faci in mice showed an increase in intestinal fat absorption. In accordance with this, Faci deficiency aggravated high-fat diet-induced obesity, hyperlipidemia, steatosis, and other obesity-related metabolic dysfunction in mice., Conclusions: FACI is a novel CREB-H-induced protein. Genetic disruption of Faci in mice showed its inhibitory effect on fat absorption and obesity. Our findings shed light on a new target of CREB-H implicated in lipid homeostasis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)