ATFormer: Advanced transformer for medical image segmentation

Combining transformers and convolutional neural networks is considered one of the most important directions for tackling medical image segmentation problems. To learn the long-range dependencies and local contexts, previous approaches embedded a convolutional layer into feedforward neural network inside the transformer block. However, a common issue is the instability during training since large differences in amplitude across layers by pre-layer normalization. Furthermore, multi-scale features were directly fused using the transformer from the encoder to decoder, which could disrupt valuable information for segmentation. To address these concerns, we propose Advanced TransFormer (ATFormer), a novel hybrid architecture that combines convolutional neural networks and transformers for medical image segmentation. First, the traditional transformer block has been refined into an Advanced Transformer Block, which adopts post-layer normalization to obtain mild activation values and employs the scaled cosine attention with shifted window for accurate spatial information. Second, the Progressive Guided Fusion module is introduced to make multi-scale features more discriminative while reducing the computational complexity. Experimental results on the ACDC, COVID-19 CT-Seg, and Tumor datasets demonstrate the significant advantage of ATFormer over existing methods that rely solely on convolutional neural networks, transformers, or their combination.

Mechanistic investigation of direct photodegradation of chloroquine phosphate under simulated sunlight.

Chloroquine phosphate (CQ) is an antiviral drug for Coronavirus Disease 2019 and an old drug for treatment of malaria, which has been detected in natural waters. Despite its prevalence, the environmental fate of CQ remains unclear. In this study, the direct photodegradation of CQ under simulated sunlight was investigated. The effect of various parameters such as pH, initial concentration and environmental matrix were examined. The photodegradation quantum yield of CQ (4.5 × 10-5-0.025) increased with the increasing pH value in the range of 6.0-10.0. The electron spin resonance (ESR) spectrometry and quenching experiments verified that the direct photodegradation of CQ was primarily associated with excited triplet states of CQ (3CQ*). The common ions had negligible effect and humic substances exhibited a negative effect on CQ photodegradation. The photoproducts were identified using high-resolution mass spectrometry and the photodegradation pathway of CQ was proposed. The direct photodegradation of CQ involved the cleavage of the C-Cl bond and substitution of the hydroxyl group, followed by further oxidation to yield carboxylic products. The photodegradation processes were further confirmed by the density functional theory (DFT) computation for the energy barrier of CQ dichlorination. The findings contribute to the assessment of the ecological risk associated with the overuse of Coronavirus drugs during global public health emergencies.

In situ architecture and membrane fusion of SARS-CoV-2 Delta variant.

Among the current five Variants of Concern, infections caused by SARS-CoV-2 B.1.617.2 (Delta) variant are often associated with the greatest severity. Despite recent advances on the molecular basis of elevated pathogenicity using recombinant proteins, the architecture of intact Delta virions remains veiled. Moreover, pieces of molecular evidence for the detailed mechanism of S-mediated membrane fusion are missing. Here, we showed the pleomorphic nature of Delta virions from electron beam inactivated samples and reported the in situ structure and distribution of S on the authentic Delta variant. We also captured the virus-virus fusion events, which provided pieces of structural evidence for Delta's attenuated dependency on cellular factors for fusion activation, and proposed a model of S-mediated membrane fusion. Besides, site-specific glycan analysis revealed increased oligomannose-type glycosylation of native Delta S than that of the WT S. Together, these results disclose distinctive factors of Delta being the most virulent SARS-CoV-2 variant.

A portable thermostatic molecular diagnosis device based on high-efficiency photothermal conversion material for rapid field detection of SARS-CoV-2

The outbreak of the novel coronavirus (SARS-CoV-2) has seriously harmed human health and economic development worldwide. Studies have shown that timely diagnosis and isolation are the most effective ways to prevent the spread of the epidemic. However, the current polymerase chain reaction (PCR) based molecular diagnostic platform has the problems of expensive equipment, high operation difficulty, and the need for stable power resources support, so it is difficult to popularize in low-resource areas. This study established a portable (<300 g), low-cost (<$10), and reusable molecular diagnostic device based on solar energy photothermal conversion strategy, which creatively introduces a sunflower-like light tracking system to improve light utilization, making the device suitable for both high and low-light areas. The experimental results show that the device can detect SARS-CoV-2 nucleic acid samples as low as 1 aM within 30 min. Graphical abstract Image 1

Ionizable drug delivery systems for efficient and selective gene therapy.

Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function. However, a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells. To be excited, the development of ionizable drug delivery systems (IDDSs) has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019 (COVID-19) in 2021. Compared with conventional cationic gene vectors, IDDSs can decrease the toxicity of carriers to cell membranes, and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures. Despite the progress, there remain necessary requirements for designing more efficient IDDSs for precise gene therapy. Herein, we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms. The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of pDNA and four kinds of RNA. In particular, organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity. We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future, and indicate ideas for developing next generation gene vectors.

An aM-level sensitive cascade CRISPR-Dx system (ASCas) for rapid detection of RNA without pre-amplification.

The CRISPR/Cas system is known as one of the directions of the next generation of mainstream molecular diagnostic technology. However, most current CRISPR/Cas molecular diagnostics still rely on the pre-amplification of nucleic acid due to the limited sensitivity of CRISPR/Cas alone, which has no significant advantage over commercial Taqman-PCR and TwistAmp® Exo kits. Herein, we report an aM-level sensitive cascade CRISPR-Dx system (ASCas) that eliminates nucleic acid pre-amplification, thus avoiding aerosol contamination and greatly reducing the testing environment and personnel skill requirements for molecular diagnostics. Most importantly, the Cas13a nucleases with high sensitivity and trans-cleavage efficiency can rapidly cleaved RNA bubbles on the hybridized cascade probe at low concentration target RNA detection, which results in the destruction of the cascade probe and releases a large amount of trigger DNA for further signal amplification of secondary Cas12a reactions. Therefore, the ASCas system achieves amplification-free, ultra-sensitivity (1 aM), and ultra-fast (20 min) RNA detection. In addition, the ASCas system replaces the complicated screening process of primers and probes with the programmed Cas13a-crRNA design so that a suitable detection system can be constructed more quickly and straightforwardly for the mutation-prone SARS-CoV-2 virus.

Covid-19 Pandemic Strategy for Treatment of Acute Uncomplicated Appendicitis with Antibiotics- Risk Categorization and Shared Decision-Making.

BACKGROUND: During the Coronavirus disease 2019 (COVID-19) pandemic, a protocol was adopted by our department on antibiotics treatment for Acute Uncomplicated Appendicitis (AUA). Our study aimed to determine the feasibility and safety of non-operative treatment (NOT), compared to upfront laparoscopic appendectomy (LA), for AUA in children during the pandemic. METHOD: Our prospective comparative study was conducted from May 1, 2020 to January 31, 2021. Patient selection criteria included: age ≥5 years, abdominal pain duration ≤48 h, ultrasound (US)/Computered Tomography scan confirmation of AUA, US appendiceal diameter 6-11 mm with no features of perforation/abscess collection and no faecolith. For NOT patients, intravenous antibiotics were administered for 24-48 h followed by oral for 10-day course. Comparison was performed between patients whose parents preferred NOT to those who opted for up-front appendectomy. Primary outcomes were NOT success at index admission, early and late NOT failure rates till 27 months. Secondary outcomes were differences in complication rate, hospital length of stay (LOS) and cost between groups. RESULTS: 77 patients were recruited: 43 (55.8%) underwent NOT while 34 (44.2%) patients opted for LA. Success of NOT at index admission was 90.7% (39/43). Overall, NOT failure rate at 27 months' follow-up was 37.2% (16/43). Of the NOT failures, 1 appendix was normal on histology while only 1 was perforated. There were no significant differences in secondary outcomes between both groups except for LOS of late NOT failure. Cost for upfront LA was nearly thrice that of NOT. CONCLUSION: Our stringent COVID protocol together with shared decision-making with parents is a safe and feasible treatment option during a crisis situation. LEVEL OF EVIDENCE: Treatment study, Level II.

A portable thermostatic molecular diagnosis device based on high-efficiency photothermal conversion material for rapid field detection of SARS-CoV-2.

The outbreak of the novel coronavirus (SARS-CoV-2) has seriously harmed human health and economic development worldwide. Studies have shown that timely diagnosis and isolation are the most effective ways to prevent the spread of the epidemic. However, the current polymerase chain reaction (PCR) based molecular diagnostic platform has the problems of expensive equipment, high operation difficulty, and the need for stable power resources support, so it is difficult to popularize in low-resource areas. This study established a portable (<300 g), low-cost (<$10), and reusable molecular diagnostic device based on solar energy photothermal conversion strategy, which creatively introduces a sunflower-like light tracking system to improve light utilization, making the device suitable for both high and low-light areas. The experimental results show that the device can detect SARS-CoV-2 nucleic acid samples as low as 1 aM within 30 min.

Understanding pediatric long COVID using a tree-based scan statistic approach: an EHR-based cohort study from the RECOVER Program.

Objectives: Post-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect conditions and symptoms associated with pediatric PASC. Materials and Methods: We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) (N = 1309) to children with (N = 6545) and without (N = 6545) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls. Results: We found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise. Discussion: Our study addresses methodological limitations of prior studies that rely on prespecified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes. Conclusion: We identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation.

The Effects of Frequent Coffee Drinking on Female-Dominated Healthcare Workers Experiencing Musculoskeletal Pain and a Lack of Sleep.

Previous research has demonstrated that chronic diseases can occur due to musculoskeletal (MS) pain and poor sleep. It is also worth noting that the caffeine in coffee can reduce overall sleep duration, efficiency, and quality. Thus, the present study examines the effects of frequent coffee drinking (two cups per day) on individuals experiencing MS pain and a lack of sleep during the COVID-19 period. This observational and cross-sectional study recruited 1615 individuals who completed the self-reported (Nordic musculoskeletal) questionnaire. Long-term, frequent coffee drinking and a sleep duration of less than 6 h per day were significantly associated with neck and shoulder pain among healthy individuals. The mediation model demonstrated that the shorter sleep duration and drinking multiple cups of coffee per day had a two-way relationship that worsened such pain over the long term. Specifically, individuals who experienced such pain frequently drank multiple cups of coffee per day, which, in turn, shortened their sleep durations. In summary, long-term coffee drinking creates a vicious cycle between MS pain and sleep duration. Therefore, the amount of coffee should be fewer than two cups per day for individuals who sleep less than 6 h per day or suffer from MS pain, especially neck and shoulder pain.

Analytical performance of rapid nucleic acid detection assays and routine RT-qPCR assays for detection of SARS-CoV-2 in Shanghai, China in 2022.

Diagnostic accuracy of COVID-19 varies among different assays. In this study, the analytical performance of 1 rapid nucleic acid detection assay (Coyote assay) and 2 routine RT-qPCR assays (BioGerm assay and DaAn assay) was evaluated, using 1196 clinical samples. Disagreement in the results of 2 paired targets occurred in all 3 assays. The Coyote assay failed to detect 15 samples, and the DaAn assay failed to detect 5 samples. The Cohen's kappa coefficient was 0.970 between the BioGerm and DaAn assays, 0.907 between the Coyote and BioGerm assays, and 0.936 between the Coyote and DaAn assays. The positive percent agreement, and negative percent agreement of the Coyote assay were 84.04%, and 100%, respectively. Our study revealed that the results of the Coyote, BioGerm, and DaAn assays were highly consistent, which provided reference for the application of these assays for diagnosis of COVID-19.

Conservative antibiotic treatment of pediatric acute uncomplicated appendicitis during the COVID-19 pandemic: a prospective comparative cohort study.

BACKGROUND: Our study aimed to compare the clinical outcomes and cost-efficiency of antibiotic management versus laparoscopic appendectomy for acute uncomplicated appendicitis (AUA) in children during the COVID-19 pandemic when resources were limited and transmission risks uncertain. METHOD: In this prospective comparative cohort study, we analyzed the data of 139 children diagnosed with AUA meeting the following inclusion criteria: 5-18 years of age, symptoms duration of ≤ 48 h, appendix diameter ≤ 11 mm and no appendicolith. Treatment outcomes between non-operative management group (78/139) and upfront laparoscopic appendectomy group (61/139) were compared. Antibiotic regimes were intravenous ceftriaxone/metronidazole or amoxicillin/clavulanic acid for 48 h, followed by oral antibiotics to complete total 10-days course. RESULTS: 8/78 (10.3%) children had early failure (within 48 h) requiring appendectomy. 17/70 (24.3%) patients experienced late recurrence within mean follow-up time of 16.2 ± 4.7 months. There were no statistical differences in peri-operative complications, negative appendicectomy rate, and incidence of perforation and hospitalization duration between antibiotic and surgical treatment groups. Cost per patient in upfront surgical group was significantly higher ($6208.5 ± 5284.0) than antibiotic group ($3588.6 ± 3829.8; p = 0.001). CONCLUSION: Despite 24.3% risk of recurrence of appendicitis in 16.2 ± 4.7 months, antibiotic therapy for AUA appears to be a safe and cost-effective alternative to upfront appendectomy.

SARS-CoV-2 Sequelae and Postdischarge Health Care Visits Over 5 Months Follow-up Among Children Hospitalized for COVID-19 or MIS-C.

Although post-acute sequelae of COVID-19 among adult survivors has gained significant attention, data in children hospitalized for severe acute respiratory syndrome coronavirus 2 is limited. This study of commercially insured US children shows that those hospitalized with COVID-19 or multisystem inflammatory syndrome in children have a substantial burden of severe acute respiratory syndrome coronavirus 2 sequelae and associated health care visits postdischarge.

A bibliometric analysis of autophagy in lung diseases from 2012 to 2021.

Background: Autophagy refers to the process in which cells wrap their damaged organelles or unwanted proteins into a double-membrane structure and direct them to lysosomes for degradation. Autophagy can regulate many lung diseases such as pulmonary hypertension, acute lung injury, and lung cancer. However, few bibliometric studies on autophagy are available. The aim of the present study was to clarify the role of autophagy in lung diseases by bibliometric analysis. Methods: Publications were retrieved from the 2012-2021 Science Citation Index Expanded of Web of Science Core Collection on 20 September 2022. Bibliometrix package in R software was used for data retrieval. VOSviewer and CiteSpace were used to visualize the research focus and trend regarding the effect of autophagy on lung disease. Results: A total of 4,522 original articles and reviews on autophagy in lung diseases published between 2012 and 2021 were identified. China had the largest number of published papers and citations, whereas the United States (US) ranked first in the H-index and G-index. Moreover, cooperation network analysis showed close cooperation between the US, China, and some European countries, and the top 10 affiliates were all from these countries and regions. Bibliometric analysis showed that "autophagy" and "apoptosis" were the keywords with the highest frequency. During the past decade, most studies were concerned with basic research on pathways related to the regulatory role of autophagy in the inhibition and attenuation of lung diseases. Conclusion: The study of autophagy in lung diseases is still in the development stage. The information published in these articles has helped researchers understand further the hot spots and development trends in the field more and learn about the collaboration network information regarding authors, countries, and institutions, as well as the paper citation correlation. More studies have been performed to gain deeper insights into the pathogenesis of autophagy by focusing on the links and effects between various diseases. More recently, research in this field has paid increasing attention to the function of autophagy in COVID-19-related lung diseases.

Optimizing national border reopening policies in the COVID-19 pandemic: A modeling study.

Objective: After emergence of the COVID-19 pandemic and subsequent restrictions, countries worldwide have sought to reopen as quickly as possible. However, reopening involves the risk of epidemic rebound. In this study, we investigated the effective policy combination to ensure safe reopen. Methods: On the basis of the classical SEIR epidemic model, we constructed a COVID-19 system dynamics model, incorporating vaccination, border screening, and fever clinic unit monitoring policies. The case of China was used to validate the model and then to test policy combinations for safe reopening. Findings: Vaccination was found to be crucial for safe reopening. When the vaccination rate reached 60%, the daily number of newly confirmed COVID-19 cases began to drop significantly and stabilized around 1,400 [1/1,000,000]. The border screening policy alone only delayed epidemic spread for 8 days but did not reduce the number of infections. Fever clinic unit monitoring alone could reduce the peak of new confirmed cases by 44% when the case identification rate rose from 20 to 80%. When combining polices, once the vaccination rate reached 70%, daily new confirmed cases stabilized at 90 [0.64/1,000,000] with an 80% case identification rate at fever clinic units and border screening. For new variants, newly confirmed cases did not stabilize until the vaccination rate reached 90%. Conclusion: High vaccination rate is the base for reopening. Vaccination passport is less effective compared with a strong primary care monitoring system for early detection and isolation of the infected cases.

Developing a conceptual framework for the health protection of United Nations peacekeepers against the COVID-19 pandemic from global health perspectives.

The coronavirus disease 2019 (COVID-19) pandemic has posed particular health risks to United Nations peacekeepers, which require prompt responses and global attention. Since the health protection of United Nations peacekeepers against the COVID-19 pandemic is a typical global health problem, strategies from global health perspectives may help address it. From global health perspectives, and referring to the successful health protection of the Chinese Anti-Ebola medical team in Liberia, a conceptual framework was developed for the health protection of United Nations peacekeepers against the COVID-19 pandemic. Within this framework, the features include multiple cross-borders (cross-border risk factors, impact, and actions); multiple risk factors (Social Determinants of Health), multiple disciplines (public health, medicine, politics, diplomacy, and others), and extensive interdepartmental cooperation. These strategies include multiple phases (before-deployment, during-deployment, and post-deployment), multi-level cooperation networks (the United Nations, host countries, troop-contributing countries, the United Nations peacekeeping team, and United Nations peacekeepers), and concerted efforts from various dimensions (medical, psychological, and social).

Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants.

To explore the mechanistic origin that determines the binding affinity of SARS-CoV-2 spike receptor binding domain (RBD) to human angiotensin converting enzyme 2 (ACE2), we constructed the homology models of RBD-ACE2 complexes of four Omicron subvariants (BA.1, BA.2, BA.3 and BA.4/5), and compared them with wild type complex (RBDWT-ACE2) in terms of various structural dynamic properties by molecular dynamics (MD) simulations and binding free energy (BFE) calculations. The results of MD simulations suggest that the RBDs of all the Omicron subvariants (RBDOMIs) feature increased global structural fluctuations when compared with RBDWT. Detailed comparison of BFE components reveals that the enhanced electrostatic attractive interactions are the main determinant of the higher ACE2-binding affinity of RBDOMIs than RBDWT, while the weakened electrostatic attractive interactions determine RBD of BA.4/5 subvariant (RBDBA.4/5) lowest ACE2-binding affinity among all Omicron subvariants. The per-residue BFE decompositions and the hydrogen bond (HB) networks analyses indicate that the enhanced electrostatic attractive interactions are mainly through gain/loss of the positively/negatively charged residues, and the formation or destruction of the interfacial HBs and salt bridges can also largely affect the ACE2-binding affinity of RBD. It is worth pointing out that since Q493R plays the most important positive contribution in enhancing binding affinity, the absence of this mutation in RBDBA.4/5 results in a significantly weaker binding affinity to ACE2 than other Omicron subvariants. Our results provide insight into the role of electrostatic interactions in determining of the binding affinity of SARS-CoV-2 RBD to human ACE2.

Effect of Marriage on Burnout among Healthcare Workers during the COVID-19 Pandemic.

Since the onset of the COVID-19 pandemic, burnout symptoms have been prevalent among healthcare workers. Living with spouses can be complex and was associated with an increased burnout risk during the COVID-19 pandemic. This study investigated the relationship between living with spouses and burnout among healthcare workers during the COVID-19 pandemic. We distributed questionnaires to participants working in a hospital affiliated with a medical university in Taiwan. The questionnaires were the Copenhagen Burnout Inventory, which comprises personal burnout (PB), work-related burnout (WB), and client burnout subscales; the Nordic Musculoskeletal Questionnaire; and information on basic demographic variables, family factors, living habits, work-related factors, and physical health factors. Multiple linear regression and mediation analysis were used. We obtained 1615 (63.81%) valid questionnaires. After analysis revealed that marriage was an independent risk factor for PB; however, the effect of marriage on WB was nonsignificant after controlling for risk factors. Parenthood, less alcohol use, reported sleep duration less than six hours, less overtime, less shift work, and participation in leisure activities with family and friends were found to be mediators between marriage and a lower WB level. In addition, chronic diseases, frequent neck pain, and shoulder pain were suppression factors. In summary, marriage was associated with an increased risk of PB. Married individuals sustain a high WB level because of changes in family roles, living conditions, and work conditions. Overall, helping healthcare workers to maintain well-being in marriage or family living may be effective in decreasing burnout during the COVID-19 pandemic.