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Telemedicine, the use of telecommunications to deliver health services, expertise and information, is a promising but unproven tool for improving the quality of diabetes care. We summarized the effectiveness of different methods of telemedicine for the management of diabetes compared with usual care. We searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials databases (to November 2015) and reference lists of existing systematic reviews for randomized controlled trials (RCTs) comparing telemedicine with usual care for adults with diabetes. Two independent reviewers selected the studies and assessed risk of bias in the studies. The primary outcome was glycated hemoglobin (HbA1C) reported at 3 time points (≤ 3 mo, 4–12 mo and > 12 mo). Other outcomes were quality of life, mortality and episodes of hypoglycemia. Trials were pooled using randomeffects meta-analysis, and heterogeneity was quantified using the I2 statistic. From 3688 citations, we identified 111 eligible RCTs (n = 23 648). Telemedicine achieved significant but modest reductions in HbA1C in all 3 follow-up periods (difference in mean at ≤ 3 mo: −0.57%, 95% confidence interval [CI] −0.74% to −0.40% [39 trials]; at 4–12 mo: −0.28%, 95% CI −0.37% to −0.20% [87 trials]; and at > 12 mo: −0.26%, 95% CI −0.46% to −0.06% [5 trials]). Quantified heterogeneity (I2 statistic) was 75%, 69% and 58%, respectively. In meta-regression analyses, the effect of telemedicine on HbA1C appeared greatest in trials with higher HbA1C concentrations at baseline, in trials where providers used Web portals or text messaging to communicate with patients and in trials where telemedicine facilitated medication adjustment. Telemedicine had no convincing effect on quality of life, mortality or hypoglycemia. Compared with usual care, the addition of telemedicine, especially systems that allowed medication adjustments with or without text messaging or a Web portal, improved HbA1C but not other clinically relevant outcomes among patients with diabetes.

The Omicron (B.1.1.529) variant of SARS-CoV-2 emerged in November 2021 and is rapidly spreading among the human population 1 . Although recent reports reveal that the Omicron variant robustly escapes vaccine-associated and therapeutic neutralization antibodies 2 – 10 , the pathogenicity of the virus remains unknown. Here we show that the replication of Omicron is substantially attenuated in human Calu3 and Caco2 cells. Further mechanistic investigations reveal that Omicron is inefficient in its use of transmembrane serine protease 2 (TMPRSS2) compared with wild-type SARS-CoV-2 (HKU-001a) and previous variants, which may explain its reduced replication in Calu3 and Caco2 cells. The replication of Omicron is markedly attenuated in both the upper and lower respiratory tracts of infected K18-hACE2 mice compared with that of the wild-type strain and Delta (B.1.617.2) variant, resulting in its substantially ameliorated lung pathology. Compared with wild-type SARS-CoV-2 and the Alpha (B.1.1.7), Beta (1.351) and Delta variants, infection by Omicron causes the lowest reduction in body weight and the lowest mortality rate. Overall, our study demonstrates that the replication and pathogenicity of the Omicron variant of SARS-CoV-2 in mice is attenuated compared with the wild-type strain and other variants. The replication and pathogenicity of the Omicron variant of SARS-CoV-2 is attenuated compared with the original strain and other variants.

SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared with its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated the immune resistance of SARS-CoV-2 JN.1 but additional factors are speculated to contribute to its global dominance, which remain elusive until today. Here, we find that SARS-CoV-2 JN.1 has a higher infectivity than BA.2.86 in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, we demonstrate that the gained infectivity of SARS-CoV-2 JN.1 over BA.2.86 associates with increased entry efficiency conferred by L455S and better spike cleavage in hNECs. Structurally, S455 altered the mode of binding of JN.1 spike protein to ACE2 when compared to BA.2.86 spike at ACE2 H34 , and modified the internal structure of JN.1 spike protein by increasing the number of hydrogen bonds with neighboring residues. These findings indicate that a single mutation (L455S) enhances virus entry in hNECs and increases immune evasiveness, which contribute to the robust transmissibility of SARS-CoV-2 JN.1. We further evaluate the in vitro and in vivo virological characteristics between SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3, and identify key lineage-specific features of the two Omicron sublineages that contribute to our understanding on Omicron antigenicity, transmissibility, and pathogenicity. Here, the authors show that a single mutation in JN.1 spike, L455S, confers better spike cleavage and enhances virus infectivity in differentiated primary human nasal epithelial cells while increasing immune evasiveness, contributing to the efficient spread of JN.1.

SARS-CoV-2 B.1.1.529.1 (Omicron BA.1) emerged in November 2021 and quickly became the predominant circulating SARS-CoV-2 variant globally. Omicron BA.1 contains more than 30 mutations in the spike protein, which contribute to its altered virological features when compared to the ancestral SARS-CoV-2 or previous SARS-CoV-2 variants. Recent studies by us and others demonstrated that Omicron BA.1 is less dependent on transmembrane serine protease 2 (TMPRSS2), less efficient in spike cleavage, less fusogenic, and adopts an altered propensity to utilize the plasma membrane and endosomal pathways for virus entry. Ongoing studies suggest that these virological features of Omicron BA.1 are in part retained by the subsequent Omicron sublineages. However, the exact spike determinants that contribute to these altered features of Omicron remain incompletely understood. In this study, we investigated the spike determinants for the observed virological characteristics of Omicron. By screening for the individual changes on Omicron BA.1 and BA.2 spike, we identify that 69-70 deletion, E484A, and H655Y contribute to the reduced TMPRSS2 usage while 25-27 deletion, S375F, and T376A result in less efficient spike cleavage. Among the shared spike mutations of BA.1 and BA.2, S375F and H655Y reduce spike-mediated fusogenicity. Interestingly, the H655Y change consistently reduces serine protease usage while increases the use of endosomal proteases. In keeping with these findings, the H655Y substitution alone reduces plasma membrane entry and facilitates endosomal entry when compared to SARS-CoV-2 WT. Overall, our study identifies key changes in Omicron spike that contributes to our understanding on the virological determinant and pathogenicity of Omicron.

Coronaviruses have caused three major endemics in the past two decades. Alarmingly, recent identification of novel zoonotic coronaviruses that caused human infections suggests the risk of future coronavirus outbreak caused by spillover infection from animal reservoirs remains high. Therefore, development of alternative therapeutic options with broad-spectrum anti-coronavirus activities are urgently needed. Here, we develop an orally available bispecific inhibitor, TMP1, which simultaneously targets key coronavirus replication protease M pro and the essential airway protease TMPRSS2. TMP1 shows broad-spectrum protection not only against different SARS-CoV-2 variants but also against multiple human-pathogenic coronaviruses in vitro. By using the K18-hACE2 transgenic mouse, hDPP4 knock-in mouse and golden Syrian hamster models, we demonstrate TMP1 cross-protects against highly-pathogenic coronaviruses (SARS-CoV-1, SARS-CoV-2 and MERS-CoV) in vivo and efficiently abrogates SARS-CoV-2 transmission. Through structural and mutagenesis studies, we confirm the direct interaction of TMP1 with M pro and TMPRSS2, and pinpoint the key sites of interactions. Importantly, TMP1 inhibits the infection of nirmatrelvir-resistant SARS-CoV-2 escape mutants. Together, our findings demonstrate the antiviral potential of the bispecific M pro /TMPRSS2 antiviral design against human-pathogenic coronaviruses and other emerging coronaviruses. Authors present a bispecific antiviral design targeting the virus and the host that simultaneously offers broad-spectrum protection against multiple existing transmissible human-pathogenic coronaviruses, including the Paxlovid-resistant SARS-CoV-2 mutants.

Usually taken as linguistic features by Part-Of-Speech (POS) tagging, Named Entity Recognition (NER) is a major task in Natural Language Processing (NLP). In this paper, we put forward a new comprehensive-embedding, considering three aspects, namely character-embedding, word-embedding, and pos-embedding stitched in the order we give, and thus get their dependencies, based on which we propose a new Character–Word–Position Combined BiLSTM-Attention (CWPC_BiAtt) for the Chinese NER task. Comprehensive-embedding via the Bidirectional Llong Short-Term Memory (BiLSTM) layer can get the connection between the historical and future information, and then employ the attention mechanism to capture the connection between the content of the sentence at the current position and that at any location. Finally, we utilize Conditional Random Field (CRF) to decode the entire tagging sequence. Experiments show that CWPC_BiAtt model we proposed is well qualified for the NER task on Microsoft Research Asia (MSRA) dataset and Weibo NER corpus. A high precision and recall were obtained, which verified the stability of the model. Position-embedding in comprehensive-embedding can compensate for attention-mechanism to provide position information for the disordered sequence, which shows that comprehensive-embedding has completeness. Looking at the entire model, our proposed CWPC_BiAtt has three distinct characteristics: completeness, simplicity, and stability. Our proposed CWPC_BiAtt model achieved the highest F-score, achieving the state-of-the-art performance in the MSRA dataset and Weibo NER corpus.

The receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein continues to evolve, facilitating antibody evasion. It remains unclear whether any conserved RBD epitopes persist across SARS-CoV-2 variants and whether vaccination and/or breakthrough infection (BTI) can elicit antibodies capable of targeting these conserved regions to counter future variants. Here, using a heterogeneous double-bait single B-cell sorting strategy, we identify a subset of antibodies with broad-spectrum RBD binding, including recognition of SARS-CoV-1 and emerging variants such as EG.5.1, BA.2.86, JN.1, and KP.2/3. These broadly binding antibodies (bbAbs) exhibit elevated levels of somatic hypermutation but are infrequently derived from clonally expanded B lymphocytes. Passive transfer of representative bbAbs reduces viral infection in a male hamster model. Structural analyses reveals that these bbAbs primarily target three distinct, highly conserved RBD epitopes, suggesting potential regions of future mutational pressure and highlighting the presence of conserved and immunogenic RBD conformations that may serve as a foundation for the development of broadly protective vaccines. SARS-CoV-2 continues to evolve, necessitating updated vaccines and therapeutics. Here the authors identify three broadly binding antibodies from vaccinated or infected individuals, characterize their conserved non-overlapping RBD epitopes by structural analysis and demonstrate protective effects in a hamster model.

KP.3.1.1 became a dominant successor to JN.1 by the second half of 2024 but the intrinsic pathogenicity and virological feature of KP.3.1.1 remain incompletely understood. Here, we comprehensively evaluated the pathogenesis and characteristics of KP.3.1.1 in comparison to JN.1 and other JN.1-derived variants including JN.1.7, KP.2, and KP.3. The unique S31del mutation on KP.3.1.1 spike confers further evasion to the clinically authorized mAb Pemivibart and reduces convalescent serum neutralization efficiency. Structural analysis indicates that S31del induces novel glycosylation sites that facilitates evasion of neutralizing antibodies. We further reveal that S31del significantly enhances pseudovirus entry efficiency in all evaluated cell types including the human primary nasal epithelial cells. Nevertheless, the intrinsic pathogenicity of KP.3.1.1 is similar to JN.1 and KP.3, and higher than that of JN.1.7 and KP.2 in a male hamster model. Interestingly, the increased virus infectivity conferred by S31del in KP.3.1.1 spike is counterbalanced by the NSP10 S33C mutation. Overall, our study indicates that a single spike mutation can confer both enhanced immune escape and increased viral infectivity. The opposing effects of spike and non-spike mutations highlight the complex interplay of viral genomic elements in shaping their overall fitness, and reveal the high plasticity of coronavirus evolution. KP.3.1.1 S S31del confers enhanced immune escape and increased infectivity, which is counterbalanced by NSP10 S33C. The opposing effects of these mutations highlight the complex interplay of viral genomic elements in shaping their overall fitness.

Human coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2 have recurrently emerged as significant pathogens, causing severe respiratory illnesses and presenting challenges to monoclonal antibody therapeutics due to their rapid evolution, particularly the diverse variants of SARS-CoV-2. In this study, we utilized \"Knob-into-Hole\" and \"IgG-scFv\" technologies to engineer bispecific antibodies (bsAbs) that target both the viral receptor and spike protein, enhancing their neutralization breadth and potency. Our bsAbs, combining anti-SARS-CoV-2 or anti-MERS-CoV antibodies with an anti-ACE2 antibody, demonstrated effective neutralization across a range of SARS-CoV-2 variants, SARS-CoV and MERS-CoV in both pseudovirus and authentic virus assays. Notably, the \"IgG-scFv\" bsAbs format exhibited superior binding and neutralization capabilities compared to the \"Knob-into-Hole\" configurations. The most effective of these, \"IgG-scFv\" H11B11_m336, displayed exceptional neutralization potency against a panel of 24 pseudotyped Beta-Coronaviruses, with IC values ranging from 0.001-0.183 μg/mL. Overall, our findings underscore the potential of bsAbs as an effective strategy to meet the immediate challenges posed by existing and emerging pathogens, thereby enhancing global pandemic preparedness.