What works and for whom in treating depression in older adults in deprived communities in Brazil: Findings from a causal mediation analyses of the PROACTIVE trial that overlapped with the COVID-19 pandemic (preprint)

Background: The PROACTIVE trial was a task-shared, collaborative care, psychosocial intervention that was highly effective at improving recovery from depression in older adults in Brazil that overlapped with the COVID-19 pandemic. Here we investigate mediators of the interventions effectiveness. Methods: Causal mediation analysis using interventional indirect effects, decomposed the total effect of PROACTIVE on recovery from depression (PHQ-9 less than 10), into multiple indirect effects including: dose of intervention (number of sessions and number of activities completed); social support measured through Luben Social Network Scale; perceived loneliness through the three-item UCLA questionnaire; conditions associated with frailty; and extra sessions offered to participants who did not respond to the intervention. Findings: Of the interventions total effect (difference in probability of recovery from depression between the intervention and control arms 0.211 [bias-corrected 95% CI: 0.139, 0.274]): 14% was mediated through improved conditions associated with frailty 0.030 [0.003, 0.065]); 6% through reduced loneliness (0.013 [0.001, 0.028]); and 20% through attending extra sessions for participants who did not respond to the intervention (0.042 [0.007, 0.105]). Interpretation: Our findings emphasise the importance of a home-based intervention to improve depression outcomes where participants are encouraged to self-select activities to mitigate against loneliness and are referred to primary care to manage health issues relating to frailty. Importantly, our findings suggest that offering extra sessions to participants who did not respond to the intervention shows promise in ensuring a sustained recovery from depression.

Enhanced Single-Particle Collision Electrochemistry at Polysulfide-Functionalized Microelectrodes for SARS-CoV-2 Detection.

Single-particle collision electrochemistry (SPCE) has shown great promise in biosensing applications due to its high sensitivity, high flux, and fast response. However, a low effective collision frequency and a large number of interfering substances in complex matrices limit its broad application in clinical samples. Herein, a novel and universal SPCE biosensor was proposed to realize sensitive detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on the collision and oxidation of single silver nanoparticles (Ag NPs) on polysulfide-functionalized gold ultramicroelectrodes (Ps-Au UMEs). Taking advantage of the strong interaction of the Ag-S bond, collision and oxidation of Ag NPs on the Ps-Au UME surface could be greatly promoted to generate enhanced Faraday currents. Compared with bare Au UMEs, the collision frequency of Ps-Au UMEs was increased by 15-fold, which vastly improved the detection sensitivity and practicability of SPCE in biosensing. By combining magnetic separation, liposome encapsulation release, and DNAzyme-assisted signal amplification, the SPCE biosensor provided a dynamic range of 5 orders of magnitude for spike proteins with a detection limit of 6.78 fg/mL and a detection limit of 21 TCID50/mL for SARS-CoV-2. Furthermore, SARS-CoV-2 detection in nasopharyngeal swab samples of infected patients was successfully conducted, indicating the potential of the SPCE biosensor for use in clinically relevant diagnosis.

Structural insights into Nirmatrelvir (PF-07321332)-3C-like SARS-CoV-2 protease complexation: a ligand Gaussian accelerated molecular dynamics study.

Coronavirus 3C-like protease (3CLpro) is found in SARS-CoV-2 virus, which causes COVID-19. 3CLpro controls virus replication and is a major target for target-based antiviral discovery. As reported by Pfizer, Nirmatrelvir (PF-07321332) is a competitive protein inhibitor and a clinical candidate for orally delivered medication. However, the binding mechanisms between Nirmatrelvir and 3CLpro complex structures remain unknown. This study incorporated ligand Gaussian accelerated molecular dynamics, the one-dimensional and two-dimensional potential of mean force, normal molecular dynamics, and Kramers' rate theory to determine the binding and dissociation rate constants (koff and kon) associated with the binding of the 3CLpro protein to the Nirmatrelvir inhibitor. The proposed approach addresses the challenges in designing small-molecule antiviral drugs.

A review on computational approaches that support the researches on traditional Chinese medicines (TCM) against COVID-19.

BACKGROUND: COVID-19 highly caused contagious infections and massive deaths worldwide as well as unprecedentedly disrupting global economies and societies, and the urgent development of new antiviral medications are required. Medicinal herbs are promising resources for the discovery of prophylactic candidate against COVID-19. Considerable amounts of experimental efforts have been made on vaccines and direct-acting antiviral agents (DAAs), but neither of them was fast and fully developed. PURPOSE: This study examined the computational approaches that have played a significant role in drug discovery and development against COVID-19, and these computational methods and tools will be helpful for the discovery of lead compounds from phytochemicals and understanding the molecular mechanism of action of TCM in the prevention and control of the other diseases. METHODS: A search conducting in scientific databases (PubMed, Science Direct, ResearchGate, Google Scholar, and Web of Science) found a total of 2172 articles, which were retrieved via web interface of the following websites. After applying some inclusion and exclusion criteria and full-text screening, only 292 articles were collected as eligible articles. RESULTS: In this review, we highlight three main categories of computational approaches including structure-based, knowledge-mining (artificial intelligence) and network-based approaches. The most commonly used database, molecular docking tool, and MD simulation software include TCMSP, AutoDock Vina, and GROMACS, respectively. Network-based approaches were mainly provided to help readers understanding the complex mechanisms of multiple TCM ingredients, targets, diseases, and networks. CONCLUSION: Computational approaches have been broadly applied to the research of phytochemicals and TCM against COVID-19, and played a significant role in drug discovery and development in terms of the financial and time saving.

Porcine Sapelovirus 3Cpro Inhibits the Production of Type I Interferon.

Porcine sapelovirus (PSV) is the causative pathogen of reproductive obstacles, acute diarrhea, respiratory distress, or severe polioencephalomyelitis in swine. Nevertheless, the pathogenicity and pathogenic mechanism of PSV infection are not fully understood, which hinders disease prevention and control. In this study, we found that PSV was sensitive to type I interferon (IFN-ß). However, PSV could not activate the IFN-ß promoter and induce IFN-ß mRNA expression, indicating that PSV has evolved an effective mechanism to block IFN-ß production. Further study showed that PSV inhibited the production of IFN-ß by cleaving mitochondrial antiviral signaling (MAVS) and degrading melanoma differentiation-associated gene 5 (MDA5) and TANK-binding kinase 1 (TBK1) through viral 3Cpro. In addition, our study demonstrated that PSV 3Cpro degrades MDA5 and TBK1 through its protease activity and cleaves MAVS through the caspase pathway. Collectively, our results revealed that PSV inhibits the production of type I interferon to escape host antiviral immunity through cleaving and degrading the adaptor molecules.

A general controllable release amplification strategy of liposomes for single-particle collision electrochemical biosensing.

As an important component of the COVID-19 mRNA vaccines, liposomes play a key role in the efficient protection and delivery of mRNA to cells. Herein, due to the controllable release amplification strategy of liposomes, a reliable and robust single-particle collision electrochemical (SPCE) biosensor was constructed for H9N2 avian influenza virus (H9N2 AIV) detection by combining liposome encapsulation-release strategy with immunomagnetic separation. The liposomes modified with biotin and loaded with platinum nanoparticles (Pt NPs) were used as signal probes for the first time. Biotin facilitated the coupling of biomolecules (DNA or antibodies) through the specific reaction of biotin-streptavidin. Each liposome can encapsulate multiple Pt NPs, which were ruptured under the presence of 1 × PBST (phosphate buffer saline with 0.05% Tween-20) within 2 min, and the encapsulated Pt NPs were released for SPCE experiment. The combination of immunomagnetic separation not only improved the anti-interference capabilities but also avoided the agglomeration of Pt NPs, enabling the SPCE biosensor to realize ultrasensitive detection of 18.1 fg/mL H9N2 AIV. Furthermore, the reliable SPCE biosensor was successfully applied in specific detection of H9N2 AIV in complex samples (chicken serum, chicken liver and chicken lung), which promoted the universality of SPCE biosensor and its application prospect in early diagnosis of diseases.

Hospital sewage treatment facilities witness the fighting against the COVID-19 pandemic.

Real-time evaluation of the fighting activities during a sudden unknown disaster like the COVID-19 pandemic is a critical challenge for control. This study demonstrates that the temporal variations of effluents from hospital sewage treatment facilities can be used as an effective indicator for such evaluation. Taking a typical infection-suffering city in China as an example, we found that there was an obvious decrease in effluent ammonia and COD concentrations in line with the start of city lockdown, and its temporal variations well indicated the major events happened during the pandemic control. Notably, the lagging period between the change point of effluent residual chlorine and the change points of COD and ammonia concentration coincided with a period in which there was a deficiency in local medical resources. In addition, the diurnal behavior of effluents from designated hospitals has varied significantly at different stages of the pandemic development. The effluent ammonia peaks shifted from daytime to nighttime after the outbreak of the COVID-19 pandemic, suggesting a high workload of the designated hospitals in fighting the rapidly emerging pandemic. This work well demonstrates the necessary for data integration at the wastewater-medical service nexus and highlights an unusual role of the effluents from hospital sewage treatment facilities in revealing the status of fighting the pandemic, which helps to control the pandemic.

Differential Antibody Response to Inactivated COVID-19 Vaccines in Healthy Subjects.

The appearance and magnitude of the immune response and the related factors correlated with SARS-CoV-2 vaccination need to be defined. Here, we enrolled a prospective cohort of 52 participants who received two doses of inactivated vaccines (BBIBP-CorV). Their serial plasma samples (n = 260) over 2 months were collected at five timepoints. We measured antibody responses (NAb, S-IgG and S-IgM) and routine blood parameter. NAb seroconversion occurred in 90.7% of vaccinated individuals and four typical NAb kinetic curves were observed. All of the participants who seroconverted after the first dose were females and had relatively high prevaccine estradiol levels. Moreover, those without seroconversion tended to have lower lymphocyte counts and higher serum SAA levels than those who experienced seroconversion. The NAb titers in young vaccine recipients had a significantly higher peak than those in elderly recipients. S-IgG and S-IgM dynamics were accompanied by similar trends in NAb. Here, we gained insight into the dynamic changes in NAbs and preliminarily explored the prevaccine blood parameters related to the kinetic subclasses, providing a reference for vaccination strategies.

A Biological Insight into the Susceptibility to Influenza Infection in Junior Rats by Comprehensive Analysis of lncRNA Profiles.

Long noncoding RNAs (lncRNAs) have been reported to participate in regulating many biological processes, including immune response to influenza A virus (IAV). However, the association between lncRNA expression profiles and influenza infection susceptibility has not been well elucidated. Here, we analyzed the expression profiles of lncRNAs, miRNAs, and mRNAs among IAV-infected adult rat (IAR), normal adult rat (AR), IAV-infected junior rat (IJR), and normal junior rat (JR) by RNA sequencing. Compared with differently expressed lncRNAs (DElncRNAs) between AR and IAR, 24 specific DElncRNAs were found between IJR and JR. Then, based on the fold changes and P value, the top 5 DElncRNAs, including 3 upregulated and 2 downregulated lncRNAs, were chosen to establish a ceRNA network for further disclosing their regulatory mechanisms. To visualize the differentially expressed genes in the ceRNA network, GO and KEGG pathway analysis was performed to further explore their roles in influenza infection of junior rats. The results showed that the downregulated DElncRNA-target genes were mostly enriched in the IL-17 signaling pathway. It indicated that the downregulated lncRNAs conferred the susceptibility of junior rats to IAV via mediating the IL-17 signaling pathway.

Imperfect adherence in real life: a prevention-effective perspective on adherence to daily and event-driven HIV pre-exposure prophylaxis among men who have sex with men - a prospective cohort study in Taiwan.

INTRODUCTION: Both daily and event-driven (ED) pre-exposure prophylaxis (PrEP) have been demonstrated to be highly effective among men who have sex with men (MSM). Prevention-effective adherence proposes that PrEP adherence should be aligned with the risk of HIV, which could be applied to both daily and ED PrEP adherence measurement. The objective of this study was to describe the relationship between the use of PrEP and sex events among the MSM PrEP users and identify factors associated with adherence among daily and ED MSM PrEP users. METHODS: A multicentre, observational, prospective cohort study was conducted at three hospital-based clinics in three urban cities of Taiwan from January 2018 to December 2019. MSM ages 18 years or older - at high risk of HIV acquisition and taking PrEP during the study period - were included in the analysis. MSM PrEP users were allowed to choose between daily and ED PrEP based on their preference. Data on sociodemographic characteristics, mental health, sexual behaviours, substance use and PrEP-taking behaviours were collected at each visit. RESULTS: A total of 374 MSM were included in the analysis with 1,054 visits. More than half (56%) of the PrEP users chose ED at the baseline and 150 regimen switches were reported by 21% of the participants. There was only one seroconversion documented during the study period. Most (84.2%) of the MSM PrEP users were able to adhere to PrEP during the most recent anal intercourse in the past one month. Among ED PrEP users with suboptimal adherence, the majority (81.9%) missed the pre-coital dose. In the multivariable analysis, we found that participants who switched from daily to an ED dosing regimen were associated with poorer adherence to PrEP. CONCLUSIONS: A high level of PrEP adherence was observed among the majority of MSM in a real-world setting. On the other hand, Taiwanese MSM switching from daily to ED dosing regimens were less likely to adhere to PrEP, suggesting that novel approaches focusing on a dosing switch would be necessary for MSM to improve their adherence to PrEP.

Characteristics and potential sources of wintertime air pollution in Linfen, China.

Linfen in China's Shanxi Province suffers severe air pollution in winter. Understanding the characteristics of air pollution and providing scientific support to mitigate such pollution are urgent matters. This study investigated the variations of PM2.5, PM10, NO2, SO2, O3, and CO in Linfen between December 1, 2019 and February 29, 2020. The mean concentrations of PM2.5, PM10, NO2, SO2, MDA8 (the maximum daily 8-h average) O3, and CO were 106.2, 139.4, 47.2, 41.0, 57.0 µg m-3, and 1.8 mg m-3, respectively. Large amounts of pollutants emitted by coal burning, industry, vehicles, and residents contributed to air pollution. Unfavorable meteorological conditions, such as lower temperature, weaker wind, higher relative humidity, and reduced planetary boundary layer height, made the situation worse. Fireworks and firecrackers set off to celebrate traditional Chinese festivals caused the concentration of PM pollutants to spike, with the maximum daily mean concentration of PM2.5 reached 314 µg m-3 and the peak hourly value reached 378.0 µg m-3. Suspensions of commercial and social activities due to COVID-19 reduced anthropogenic emissions, mainly from industry and transportation, which decreased the level of air pollutants other than O3. Analyses involving backward trajectory cluster, the potential source contribution function, and concentration weighted trajectory demonstrated that PM2.5 pollution mainly came from local emissions in Shanxi Province and regional transport from Inner Mongolia, Shaanxi, Hebei, Henan, and Gansu provinces. Shanxi and its surrounding provinces should adopt measures such as tightening environmental management standards, promoting the use of renewable energy, and adjusting the transportation structure to reduce regional emissions. This study will help policy-makers draft plans and policies to reduce air pollution in Linfen.

The interval between onset and admission predicts disease progression in COVID-19 patients.

BACKGROUND: The prognostic role of the interval between disease onset and hospital admission (O-A interval) was undetermined in patients with the coronavirus disease 2019 (COVID-19). METHODS: A total of 205 laboratory-confirmed inpatients admitted to Hankou hospital of Wuhan from January 11 to March 8, 2020 were consecutively included in this retrospective observational study. Demographic data, medical history, laboratory testing results were collected from medical records. Univariate and multivariate logistic regression models were used to evaluate the prognostic effect of the O-A interval (≤7 versus >7 days) on disease progression in mild-to-moderate patients. For severe-to-critical patients, the in-hospital mortality and the length of hospital stay were compared between the O-A interval subgroups using log-rank test and Mann-Whitney U test, respectively. RESULTS: Mild-to-moderate patients with a short O-A interval (≤7 days) are more likely to deteriorate to severe-to-critical stage compared to those with a long O-A interval (>7 days) [unadjusted odds ratio =2.93, 95% confidence interval (CI), 1.32-6.55; adjusted odds ratio =3.44, 95% CI, 1.20-9.83]. No association was identified between the O-A interval and the mortality or the length of hospital stay of severe-to-critical patients. CONCLUSIONS: The O-A interval has predictive values for the disease progression in mild-to-moderate COVID-19 patients. Under circumstances of the specific health system in Wuhan, China, the spontaneous healthcare-seeking behavior is usually determined by patients' own heath conditions. Hence, the O-A interval can be reflective of the natural course of COVID-19 to some extent. However, our findings should be validated further in other cohorts and in other health systems.

Turning Point during COVID-19 Pandemic: Transformation and Innovation of Infection Control in the Hospital

2019年底起源於中國武漢之新型冠狀病毒COVID-19疫情，造成全球大流行。台灣經歷17年前的SARS疫情，對COVID-19及早因應並希望能防堵於境外。COVID-19風暴下，醫療體系、醫療生態及醫療行為都需快速的轉變與因應。本文簡述在台灣防疫政策下，臺北市立聯合醫院仁愛院區面對疫情四個階段的因應作為，並探討COVID-19所帶來的衝擊與創新。第一階段，經由加強入院人員監測及開設專責病房來預防COVID-19院內感染。第二階段，加強社區COVID-19監測、提升特殊單位防護、分艙分流、及非緊急醫療服務量降載來因應可能面臨之本土社區感染。第三階段因應COVID-19全球大流行，規劃重症加護病床。第四階段為如何與COVID-19長期抗戰與共舞。在目前COVID-19尚無有效藥物及疫苗之狀況下，大流行對社會及醫療體系有極大的衝擊與崩壞之可能性。仁愛院區透過各單位水平與垂直整合，根據疫情即時、滾動式調整，建立感染管制文化，守護醫院及台灣。 The outbreak of novel coronavirus disease 2019 (COVID-19) was first reported by the end of 2019 in Wuhan, China, , and is currently causing a global pandemic. Taiwan had a SARS outbreak 17 years ago, which primed the Central Epidemic Command Center to respond to COVID-19 earlier and swiftly and keep the virus away from the country. Timely response and alteration of the healthcare systems, ecology and behaviors of daily are mandatory. This article briefly describes the four stages of Taipei City Hospital Renai Branch, Taiwan in response to the pandemic, and discusses the impact and innovation brought by COVID-19. At the first stage, nosocomial infection was prevented by strengthening of active surveillance of all admitted patients and setting up of quarantine wards for suspected COVID-19 cases. The second stage was to strengthen the community surveillance, enhance protection for health workers in special units, triage and compartmentalization, and reducing inpatient and outpatient number to respond to potential community outbreak. At the third stage, we expanded the capacity of intensive care units for isolation in response to the global pandemic. The fourth stage was to plan a long-term defense and ＂dance＂ with COVID-19. The COVID-19 pandemic may pound and break the society and healthcare systems with force in the absence of effective pharmaceutics and vaccines. The Renai branch adjusts the response strategy in a rolling style and establishes infection control culture to guide the hospital and the nation through horizontal and vertical integration.

Expression and immunoreactivity of a recombinant multi-epitope antigen designed based on four major structural proteins of avian infectious bronchitis virus.

The development of rapid, simple, and sensitive diagnostic methods for identification of avian infectious bronchitis virus (IBV) is crucial for the effective control of avian infectious bronchitis. In the present study, a tandemly arranged multiepitope peptide (named SEMN) was designed with four antigenic regions derived from four major structural proteins of IBV. Then, we performed codon optimization of SEMN gene by changing the codon-adaptation index from 0.45 to 0.94 and expressed the optimized gene in codon bias-adjusted Escherichia coli Rosetta (DE3), followed by determination of the immunoreactivity of the purified protein. Bioinformatics analysis of SEMN showed a high antigenicity, surface probability and hydrophilicity. The recombinant protein rSEMN was expressed both in soluble forms and as inclusion bodies, and the molecular weight of rSEMN was about 39 kDa. The preliminary diagnostic performance of rSEMN was confirmed by Western blotting analysis using chicken anti-IBV polyclonal antibodies. Further studies are needed to evaluate the immunogenicity in animal models and to give a final assessment of the diagnostic utility of this recombinant multi-epitope antigen.

The effectiveness and efficacy of respiratory protective equipment (RPE) in dentistry and other health care settings: a systematic review.

OBJECTIVE: The global pandemic of coronavirus disease-19, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is the latest hazard facing healthcare workers (HCW) including dental care workers (DCW). It is clear that the major mode of SARS-CoV-2 transmission is the airborne route, through inhalation of virus-infested aerosols and droplets. Several respiratory protection equipment (RPE), including masks, face shields/visors, and respirators, are available to obviate facial and conjunctival contamination by microbes. However, as their barrier value against microbial inhalation has not been evaluated, we systematically reviewed the data on the effectiveness and efficacy of facemasks and respirators, including protective eyewear, with particular emphasis on dental healthcare. MATERIAL AND METHODS: PubMed, MEDLINE, the Cochrane Library, and Embase databases were searched between 01January 1990 and 15 May 2020. RESULTS: Of 310 identified English language records, 21 were included as per eligibility criteria. In clinical terms, wearing layered, face-fitting masks/respirators and protective-eyewear can limit the spread of infection among HCWs. Specifically, combined interventions such as a face mask and a face shield, better resist bioaerosol inhalation than either alone. The prolonged and over-extended use of surgical masks compromise their effectiveness. CONCLUSIONS: In general, RPE is effective as a barrier protection against aerosolized microbes in healthcare settings. But their filtration efficacy is compromised by the (i) inhalant particle size, (ii) airflow dynamics, (iii) mask-fit factor, (iv) period of wear, (v) 'wetness' of the masks, and (vi) their fabrication quality. The macro-data presented here should inform policy formulation on RPE wear amongst HCWs.

Advance of Novel Coronavirus Registration Clinical Trial (preprint)

Background.This research aims to analyze the clinical characteristics of a novel Corona Virus Disease (COVID-19) registered in the Chinese Clinical Trial Registry (ChiCTR), and to provide an information-based data foundation and information reference for curbing the spread of the COVID-19 epidemic. Methods.The ChiCTR database was comprehensively searched, and the COVID-19 research registration information as of February 24, 2020 was counted. Descriptive analysis of registration time trends and geographical distribution. Chi-square test was used to compare the statistical differences between different study types, intervention methods, research phases and major sponsors. Frequency studies were used to analyze the characteristics of CMT and BI therapy. Results.232 COVID-19 studies registered at the ChiCTR Center were collected. The overall number of COVID-19 registrations was increased. Hubei Province, China has the largest number of registrations, followed by Guangdong, Zhejiang and Sichuan. There were significant differences between the number of participants (P=0.000), study duration (P=0.008), study assignment (P=0.000), and blind method (P=0.000) for different study types. Significant differences could be seen in the dimensions of multicenter study(P=0.022), of participants numbe(P=0.000), study duration(P=0.000) and study assignment(P=0.001) for the four intervention methods. There were significant differences in study assignment (P=0.043) between the early and late studies. CMT drugs with high research frequency are chloroquine, lopinavir / ritonavir, and I-IFN, which are all in phase 4; BI was Cell therapy, plasma therapy, Thymosin, and M/P-AB, which are all in early stages. Conclusion.There were problems of unclear classification of research types and irregular registration behavior. Also, within the studies researched, heterogeneity exists for various dimensions. Different research types, intervention methods, and research stages lead to significant differences in some dimensions of the COVID-19 study. Finally, statistical high-frequency research drugs can provide more treatment options and evidence-based evidence for the clinical practice.