C. elegans spermatocyte divisions show a weak spindle checkpoint response.

Male meiotic division exhibits two consecutive chromosome separation events without apparent pausing. Several studies have shown that spermatocyte divisions are not stringently regulated as in mitotic cells. In this study, we investigated the role of the canonical spindle assembly (SAC) pathway in Caenorhabditis elegans spermatogenesis. We found the intensity of chromosome-associated outer kinetochore protein BUB-1 and SAC effector MDF-1 oscillates between the two divisions. However, the SAC target securin is degraded during the first division and remains undetectable for the second division. Inhibition of proteasome-dependent protein degradation did not affect the progression of the second division but stopped the first division at metaphase. Perturbation of spindle integrity did not affect the duration of meiosis II, and only slightly lengthened meiosis I. Our results demonstrate that male meiosis II is independent of SAC regulation, and male meiosis I exhibits only weak checkpoint response.

Enlarged tumour-draining lymph node with immune-activated profile predict favourable survival in non-metastatic colorectal cancer.

BACKGROUND: The tumour-draining lymph node (TDLN) plays a pivotal role in the suppression of malignant tumour, however, the immunological profile and prognostic differences between large TDLN (L-TDLN) and small TDLN (S-TDLN) in colorectal cancer (CRC) remain unclear. METHODS: We conducted a study using data from the Chinese National Cancer Center (CNCC) database, identifying 837 CRC patients with non-metastatic TDLN, and categorised them into L-TDLN and S-TDLN groups. The long-term survival outcomes and adjuvant therapy efficacy were compared between the two groups. Furthermore, we evaluated the differences in immune activation status and immune cell subsets between patients in L-TDLN and S-TDLN groups by RNA sequencing and immunohistochemical (IHC) staining. RESULTS: Patients with L-TDLN demonstrated better long-term outcomes compared to those with S-TDLN. Among patients with L-TDLN, there was no significant difference in long-term outcomes between those who received adjuvant chemotherapy and those who did not. The RNA sequencing data revealed a wealth of immune-activating pathways explored in L-TDLN. Furthermore, IHC analysis demonstrated higher numbers of CD3+ and CD8 + T cells in L-TDLN and the corresponding CRC lesions, as compared to patients with S-TDLN. CONCLUSION: Enlarged TDLN exhibited an activated anti-tumour immune profile and may serve as an indicator for favourable survival in non-metastatic CRC.

Major HBV splice variant encoding a novel protein important for infection.

BACKGROUND & AIMS: HBV expresses more than 10 spliced RNAs from the viral pregenomic RNA, but their functions remain elusive and controversial. To address the function of HBV spliced RNAs, we generated splicing-deficient HBV mutants and conducted experiments to assess the impact of these mutants on HBV infection. METHODS: HepG2-NTCP cells, human hepatocyte chimeric FRG mice (hu-FRG mice), and serum from patients with chronic hepatitis B were used for experiments on HBV infection. Additionally, SHifter assays and cryo-electron microscopy were performed. RESULTS: We found the infectivity of splicing-deficient HBV was decreased 100-1,000-fold compared with that of wild-type HBV in hu-FRG mice. Another mutant, A487C, which loses the most abundant spliced RNA (SP1), also exhibits severely impaired infectivity. SP1 hypothetically encodes a novel protein HBcSP1 (HBc-Cys) that lacks the C-terminal cysteine from full-length HBc. In the SHifter assay, HBcSP1 was detected in wild-type viral particles at a ratio of about 20-100% vs. conventional HBc, as well as in the serum of patients with chronic hepatitis B, but not in A487C particles. When infection was conducted with a shorter incubation time of 4-8 h at lower PEG concentrations in HepG2-NTCP cells, the entry of the A487C mutant was significantly slower. SP1 cDNA complementation of the A487C mutant succeeded in rescuing its infectivity in hu-FRG mice and HepG2-NTCP cells. Moreover, cryo-electron microscopy revealed a disulfide bond between HBc cysteine 183 and 48 in the HBc intradimer of the A487C capsid, leading to a locked conformation that disfavored viral entry in contrast to the wild-type capsid. CONCLUSIONS: Prior studies unveiled the potential integration of the HBc-Cys protein into the HBV capsid. We confirmed the proposal and validated its identity and function during infection. IMPACT AND IMPLICATIONS: HBV SP1 RNA encodes a novel HBc protein (HBcSP1) that lacks the C-terminal cysteine from conventional HBc (HBc-Cys). HBcSP1 was detected in cell culture-derived HBV and confirmed in patients with chronic infection by both immunological and chemical modification assays at 10-50% of capsid. The splicing-deficient mutant HBV (A487C) impaired infectivity in human hepatocyte chimeric mice and viral entry in the HepG2-NTCP cell line. Furthermore, these deficiencies of the splicing-deficient mutant could be rescued by complementation with the SP1-encoded protein HBcSP1. We confirmed and validated the identity and function of HBcSP1 during infection, building on the current model of HBV particles.

Development of AAV-delivered broadly neutralizing anti-human ACE2 antibodies against SARS-CoV-2 variants.

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in the emergence of new variants that are resistant to existing vaccines and therapeutic antibodies, has raised the need for novel strategies to combat the persistent global COVID-19 epidemic. In this study, a monoclonal anti-human angiotensin-converting enzyme 2 (hACE2) antibody, ch2H2, was isolated and humanized to block the viral receptor-binding domain (RBD) binding to hACE2, the major entry receptor of SARS-CoV-2. This antibody targets the RBD-binding site on the N terminus of hACE2 and has a high binding affinity to outcompete the RBD. In vitro, ch2H2 antibody showed potent inhibitory activity against multiple SARS-CoV-2 variants, including the most antigenically drifted and immune-evading variant Omicron. In vivo, adeno-associated virus (AAV)-mediated delivery enabled a sustained expression of monoclonal antibody (mAb) ch2H2, generating a high concentration of antibodies in mice. A single administration of AAV-delivered mAb ch2H2 significantly reduced viral RNA load and infectious virions and mitigated pulmonary pathological changes in mice challenged with SARS-CoV-2 Omicron BA.5 subvariant. Collectively, the results suggest that AAV-delivered hACE2-blocking antibody provides a promising approach for developing broad-spectrum antivirals against SARS-CoV-2 and potentially other hACE2-dependent pathogens that may emerge in the future.

Betulin Accelerated the Functional Recovery of Injured Muscle in a Mouse Model of Muscle Contusion.

Muscle contusion is an injury to muscle fibers and connective tissues. It commonly happens in impact events, and could result in pain, swelling, and limited range of motion. Diclofenac is one of commonly used nonsteroidal anti-inflammatory drugs to alleviate pain and inflammation after injury. However, it can potentially cause some side effects including gastrointestinal complications and allergy. Betulin is a lupine-type pentacyclic triterpenoid. It is showed to have valuable pharmacological effects, but the physiological effect of betulin on muscle contusion has not been reported. This study aimed to explore the therapeutic effects of betulin on muscle contusion that produced by the drop-mass method in mice. C57BL/6 mice were randomly assigned to control (no injury), only drop-mass injury (Injury), diclofenac treatment (Injury+diclofenac), and betulin treatment (Injury+betulin) groups. Injury was executed on the gastrocnemius of the right hind limb, and then phosphate-buffered saline (PBS), diclofenac, or betulin were oral gavage administrated respectively for 7 days. Results revealed that betulin significantly restored motor functions based on locomotor activity assessments, rota-rod test, and footprints analysis. Betulin also attenuated serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels after muscle injury. Neutrophil infiltration was alleviated and desmin levels were increased after betulin treatment. Our data demonstrated that betulin attenuated muscle damage, alleviated inflammatory response, improved muscle regeneration, and restored motor functions after muscle contusion. Altogether, betulin may be a potential compound to accelerate the repair of injured muscle.

Does post acute care reduce the mortality of octogenarian and nonagenarian patients undergoing hip fracture surgery?

BACKGROUND: With the increasing number of elderly individuals worldwide, a greater number of people aged 80 years and older sustain fragility fracture due to osteopenia and osteoporosis. METHODS: This retrospective study included 158 older adults, with a median age of 85 (range: 80-99) years, who sustained hip fragility fracture and who underwent surgery. The patients were divided into two groups, one including patients who joined the post-acute care (PAC) program after surgery and another comprising patients who did not. The mortality, complication, comorbidity, re-fracture, secondary fracture, and readmission rates and functional status (based on the Barthel index score, numerical rating scale score, and Harris Hip Scale score) between the two groups were compared. RESULTS: The patients who presented with fragility hip fracture and who joined the PAC rehabilitation program after the surgery had a lower rate of mortality, readmission rate, fracture (re-fracture and secondary fracture), and complications associated with fragility fracture, such as urinary tract infection, cerebrovascular accident, and pneumonia (acute coronary syndrome, out-of-hospital cardiac arrest, or in-hospital cardiac arrest. CONCLUSIONS: PAC is associated with a lower rate of mortality and complications such as urinary tract infection, bed sore, and pneumonia in octogenarian and nonagenarian patients with hip fragility fracture.

An Aeromagnetic Compensation Strategy for Large UAVs.

Aeromagnetic surveys are widely used in geological exploration, mineral resource assessment, environmental monitoring, military reconnaissance, and other areas. It is necessary to perform magnetic compensation for interference in these fields. In recent years, large unmanned aerial vehicles (UAVs) have been more suitable for magnetic detection missions because of the greater loads they can carry. This article proposes some methods for the magnetic compensation of large multiload UAVs. Because of the interference of the large platform and instrument noise, the standard deviations (stds) of the compensation data used in this paper are larger. At the beginning of this article, using the traditional T-L model, we avoid the shortcomings of the anti-magnetic interference ability of triaxial magnetic gate magnetometers. The direction cosine information is obtained by using an inertial navigation system, the global positioning system, and a triaxial magnetic gate magnetometer. Then, we increase the amplitude of the maneuvers in the compensation process; this reduces the multicollinearity problems in the compensation matrix to a certain extent, but it also results in greater magnetic field interference. Lastly, we employ the method of Lasso regularization Newton iteration (LRNM). Compared to the traditional methods of least squares (LS) and singular value decomposition (SVD), LRNM provides improvements of 34% and 27%, respectively. In summary, this series of schemes can be used to perform effective compensation for large multi-load UAVs and improve the actual use of large UAVs, making them more accurate in the measurement of aeromagnetic survey data.

Poly(lactic acid hydroxyacetic acid)-poly(ethylene glycol)-modified ginsenoside Rg3 nanomedicine enhances anti-tumor effect in hepatocellular carcinoma.

OBJECTIVE: This research aims to improve the bioavailability and anti-hepatocellular carcinoma (HCC) efficacy of Ginsenoside Rg3 by modification with poly (lactic acid hydroxyacetic acid)-poly(ethylene glycol) (PLGA-PEG). METHODS: PLGA-PEG-Rg3 was obtained by emulsification and evaluated it physiochemical characterization by FTIR, SEM, laser particle-size analyzer and HPLC. The effect of the PLGA-PEG-Rg3 and Rg3 on HepG2 cells was compared in vitro studies, including cell proliferation, transwell and a series of apoptosis detection, and in-situ HCC model. RESULTS: The PLGA-PEG-Rg3 were 122 nm in size and 0.112 in polydispersity index with sustained release profile in vitro. Compared to Rg3, PLGA-PEG-Rg3 was more effective in suppressing HepG2 growth and inducing apoptosis by the mitochondrial apoptosis pathway in vitro. And PLGA-PEG modification enhanced the liver-targeting ability and drug circulation time of Rg3 in vivo, resulting in PLGA-PEG-Rg3 possessing superior performance in inhibiting tumor growth and prolonging the survival time of tumor-bearing mice than Rg3. CONCLUSIONS: Overall, these results showed PLGA-PEG-Rg3 enhanced the anti-tumor effect of Rg3 in HCC.

Efficient Regulation of Polysulfides by MoS2 /MoO3 Heterostructures for High-Performance Li-S Batteries.

The notorious shuttle effect and sluggish conversion of polysulfides seriously hinder the practical application of Lithium-sulfur (Li-S) batteries. In this study, a novel architecture of MoS2 /MoO3 heterostructure uniformly distributed on carbon nanotubes (MoS2 /MoO3 @CNT) is designed and introduced into Li-S batteries via decorating commercial separator to regulate the redox reactions of polysulfides. Systematic experiments and theoretical calculations showed that the heterostructure not only provides sufficient surface affinity to capture polysulfides and acts as an active catalyst to promote the conversion of polysulfides, but also the highly conductive CNT enables rapid electron/ion migration. As a result, Li-S batteries with the MoS2 /MoO3 @CNT-PP separator deliver an impressive reversible capacity (1015 mAh g-1 at 0.2 A g-1 after 100 cycles), excellent rate capacity (873 mAh g-1 at 5 A g-1 ), and low self-discharge capacity loss (94.6% capacity retention after 7 days of standing). Moreover, even at an elevated temperature of 70 °C, it still exhibits high-capacity retention (800 mAh g-1 at 1 A g-1 after 100 cycles). Encouragingly, when the sulfur load is increased to 8.7 mg cm-2 , the high reversible areal capacity of 6.61 mAh cm-2 can be stably maintained after 100 cycles, indicating a high potential for practical application.

Rapid generation of mouse model for emerging infectious disease with the case of severe COVID-19.

Since the pandemic of COVID-19 has intensely struck human society, small animal model for this infectious disease is in urgent need for basic and pharmaceutical research. Although several COVID-19 animal models have been identified, many of them show either minimal or inadequate pathophysiology after SARS-CoV-2 challenge. Here, we describe a new and versatile strategy to rapidly establish a mouse model for emerging infectious diseases in one month by multi-route, multi-serotype transduction with recombinant adeno-associated virus (AAV) vectors expressing viral receptor. In this study, the proposed approach enables profound and enduring systemic expression of SARS-CoV-2-receptor hACE2 in wild-type mice and renders them vulnerable to SARS-CoV-2 infection. Upon virus challenge, generated AAV/hACE2 mice showed pathophysiology closely mimicking the patients with severe COVID-19. The efficacy of a novel therapeutic antibody cocktail RBD-chAbs for COVID-19 was tested and confirmed by using this AAV/hACE2 mouse model, further demonstrating its successful application in drug development.

Structure-guided antibody cocktail for prevention and treatment of COVID-19.

Development of effective therapeutics for mitigating the COVID-19 pandemic is a pressing global need. Neutralizing antibodies are known to be effective antivirals, as they can be rapidly deployed to prevent disease progression and can accelerate patient recovery without the need for fully developed host immunity. Here, we report the generation and characterization of a series of chimeric antibodies against the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Some of these antibodies exhibit exceptionally potent neutralization activities in vitro and in vivo, and the most potent of our antibodies target three distinct non-overlapping epitopes within the RBD. Cryo-electron microscopy analyses of two highly potent antibodies in complex with the SARS-CoV-2 spike protein suggested they may be particularly useful when combined in a cocktail therapy. The efficacy of this antibody cocktail was confirmed in SARS-CoV-2-infected mouse and hamster models as prophylactic and post-infection treatments. With the emergence of more contagious variants of SARS-CoV-2, cocktail antibody therapies hold great promise to control disease and prevent drug resistance.

Mapping the conformational epitope of a therapeutic monoclonal antibody against HBsAg by in vivo selection of HBV escape variants.

BACKGROUND AND AIMS: Hepatitis B immunoglobulin (HBIG) has been routinely applied in the liver transplantation setting to block HBV reinfection of grafts. However, new monoclonal anti-HBV surface antibodies have been developed to replace HBIG. The epitopes of such monoclonal antibodies may affect the emergence of escape variants and deserve study. APPROACH AND RESULTS: The conformational epitope of sLenvervimab, a surrogate form of Lenvervimab, which is a monoclonal anti-HBsAg antibody currently under phase 3 trial, was investigated by selecting escape mutants from a human liver chimeric mouse. HBV-infected chimeric mice treated with sLenvervimab monotherapy showed an initial decline in circulating HBsAg levels, followed by a quick rebound in 1 month. Sequencing of circulating or liver HBV DNA revealed emerging variants, with replacement of amino acid E164 or T140, two residues widely separated in HBsAg. E164 HBV variants strongly resisted sLenvervimab neutralization in cell culture infection, and the T140 variant moderately resisted sLenvervimab neutralization. Natural HBV variants with amino-acid replacements adjacent to E164 were constructed and examined for sLenvervimab neutralization effects. Variants with K160 replacement also resisted neutralization. These data revealed the conformational epitope of sLenvervimab. CONCLUSIONS: Selection of antibody-escape HBV variants in human chimeric mice works efficiently. Analysis of such emerging variants helps to identify anchor amino-acid residues of the conformational epitope that are difficult to discover by conventional approaches.

Upregulation of PD-L1 by SARS-CoV-2 promotes immune evasion.

Patients with severe COVID-19 often suffer from lymphopenia, which is linked to T-cell sequestration, cytokine storm, and mortality. However, it remains largely unknown how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces lymphopenia. Here, we studied the transcriptomic profile and epigenomic alterations involved in cytokine production by SARS-CoV-2-infected cells. We adopted a reverse time-order gene coexpression network approach to analyze time-series RNA-sequencing data, revealing epigenetic modifications at the late stage of viral egress. Furthermore, we identified SARS-CoV-2-activated nuclear factor-κB (NF-κB) and interferon regulatory factor 1 (IRF1) pathways contributing to viral infection and COVID-19 severity through epigenetic analysis of H3K4me3 chromatin immunoprecipitation sequencing. Cross-referencing our transcriptomic and epigenomic data sets revealed that coupling NF-κB and IRF1 pathways mediate programmed death ligand-1 (PD-L1) immunosuppressive programs. Interestingly, we observed higher PD-L1 expression in Omicron-infected cells than SARS-CoV-2 infected cells. Blocking PD-L1 at an early stage of virally-infected AAV-hACE2 mice significantly recovered lymphocyte counts and lowered inflammatory cytokine levels. Our findings indicate that targeting the SARS-CoV-2-mediated NF-κB and IRF1-PD-L1 axis may represent an alternative strategy to reduce COVID-19 severity.

Acute generation of reactive oxygen species that induced by doxycycline pretreatment results in rapid cell death in polyphyllin G-treated osteosarcoma cell lines.

Polyphyllin G, a pennogenyl saponin extracted from Paris polyphylla, has been shown to possess antitumor effects. In this study, we demonstrated that doxycycline, an antibiotic medicine, could significantly enhance the sensitivities of osteosarcoma cell lines to polyphyllin G. As the cells were pretreated with doxycycline at non-toxic concentrations and then co-exposed to polyphyllin G, this combination could induce a rapid cell death distinct from apoptosis. The non-apoptotic cell death was characterized by a loss of integrity of plasma membrane without externalization of phosphatidyl serine. Furthermore, this combined treatment resulted in suppression of cell viability and colony-forming ability, and increased the level of γ-H2A.X, a critical marker for DNA damage, in osteosarcoma cell lines. When examining the underlying mechanism, it was revealed combination of polyphyllin G and doxycycline triggered an enhanced generation of reactive oxygen species (ROS), and up-regulated mitochondrial oxidative stress within 0.5 h. Co-administration of the ROS inhibitor NAC reversed the suppressed cell viability and colony-forming ability, and abolished the increased level of γ-H2A.X in the cells with the combined treatment, indicating that the enhanced ROS was involved in the anti-proliferative effect of the combined treatment. Overall, the results demonstrated that doxycycline may function as chemosensitizers by inducing an acute and lethal ROS production to enhance cytotoxic of polyphyllin G in osteosarcoma cell lines, and the combined use of drugs may provide an alternative thinking for the development of new therapeutic agents.

Clinical Implications of HBV PreS/S Mutations and the Effects of PreS2 Deletion on Mitochondria, Liver Fibrosis, and Cancer Development.

BACKGROUND AND AIMS: PreS mutants of HBV have been reported to be associated with HCC. We conducted a longitudinal study of the role of HBV preS mutations in the development of HCC, particularly in patients with chronic hepatitis B (CHB) having low HBV DNA or alanine aminotransferase (ALT) levels, and investigated the effects of secretion-defective preS2 deletion mutant (preS2ΔMT) on hepatocyte damage in vitro and liver fibrosis in vivo. APPROACH AND RESULTS: Association of preS mutations with HCC in 343 patients with CHB was evaluated by a retrospective case-control follow-up study. Effects of preS2ΔMT on HBsAg retention, endoplasmic reticulum (ER) stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed a significant association of preS mutations with HCC (HR, 3.210; 95% CI, 1.072-9.613; P = 0.037) including cases with low HBV DNA or ALT levels (HR, 2.790; 95% CI, 1.133-6.873; P = 0.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. PreS2ΔMT expression promoted HBsAg retention in the ER and unfolded protein response (UPR). Transmission electron microscopic examination, MitoTracker staining, real-time ATP assay, and calcium staining of preS2ΔMT-expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100-fold lower in preS2ΔMT-infected humanized Fah-/-/ Rag2-/-/Il2rg-/- triple knockout mice than in wild-type HBV-infected mice. PreS2ΔMT-infected mice displayed up-regulation of UPR and caspase-3 and enhanced liver fibrosis. CONCLUSIONS: PreS mutations were significantly associated with HCC development in patients with CHB, including those with low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in patients with CHB, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.

CLEC5A and TLR2 are critical in SARS-CoV-2-induced NET formation and lung inflammation.

BACKGROUND: Coronavirus-induced disease 19 (COVID-19) infects more than three hundred and sixty million patients worldwide, and people with severe symptoms frequently die of acute respiratory distress syndrome (ARDS). Recent studies indicated that excessive neutrophil extracellular traps (NETs) contributed to immunothrombosis, thereby leading to extensive intravascular coagulopathy and multiple organ dysfunction. Thus, understanding the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation would be helpful to reduce thrombosis and prevent ARDS in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We incubated SARS-CoV-2 with neutrophils in the presence or absence of platelets to observe NET formation. We further isolated extracellular vesicles from COVID-19 patients' sera (COVID-19-EVs) to examine their ability to induce NET formation. RESULTS: We demonstrated that antagonistic mAbs against anti-CLEC5A mAb and anti-TLR2 mAb can inhibit COVID-19-EVs-induced NET formation, and generated clec5a-/-/tlr2-/- mice to confirm the critical roles of CLEC5A and TLR2 in SARS-CoV-2-induced lung inflammation in vivo. We found that virus-free extracellular COVID-19 EVs induced robust NET formation via Syk-coupled C-type lectin member 5A (CLEC5A) and TLR2. Blockade of CLEC5A inhibited COVID-19 EVs-induced NETosis, and simultaneous blockade of CLEC5A and TLR2 further suppressed SARS-CoV-2-induced NETosis in vitro. Moreover, thromboinflammation was attenuated dramatically in clec5a-/-/tlr2-/- mice. CONCLUSIONS: This study demonstrates that SARS-CoV-2-activated platelets produce EVs to enhance thromboinflammation via CLEC5A and TLR2, and highlight the importance of CLEC5A and TLR2 as therapeutic targets to reduce the risk of ARDS in COVID-19 patients.

A critical overview of current progress for COVID-19: development of vaccines, antiviral drugs, and therapeutic antibodies.

The novel coronavirus disease (COVID-19) pandemic remains a global public health crisis, presenting a broad range of challenges. To help address some of the main problems, the scientific community has designed vaccines, diagnostic tools and therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of technology development, especially with regard to vaccines, represents a stunning and historic scientific achievement. Nevertheless, many challenges remain to be overcome, such as improving vaccine and drug treatment efficacies for emergent mutant strains of SARS-CoV-2. Outbreaks of more infectious variants continue to diminish the utility of available vaccines and drugs. Thus, the effectiveness of vaccines and drugs against the most current variants is a primary consideration in the continual analyses of clinical data that supports updated regulatory decisions. The first two vaccines granted Emergency Use Authorizations (EUAs), BNT162b2 and mRNA-1273, still show more than 60% protection efficacy against the most widespread current SARS-CoV-2 variant, Omicron. This variant carries more than 30 mutations in the spike protein, which has largely abrogated the neutralizing effects of therapeutic antibodies. Fortunately, some neutralizing antibodies and antiviral COVID-19 drugs treatments have shown continued clinical benefits. In this review, we provide a framework for understanding the ongoing development efforts for different types of vaccines and therapeutics, including small molecule and antibody drugs. The ripple effects of newly emergent variants, including updates to vaccines and drug repurposing efforts, are summarized. In addition, we summarize the clinical trials supporting the development and distribution of vaccines, small molecule drugs, and therapeutic antibodies with broad-spectrum activity against SARS-CoV-2 strains.

A booster dose of Delta × Omicron hybrid mRNA vaccine produced broadly neutralizing antibody against Omicron and other SARS-CoV-2 variants.

BACKGROUND: With the continuous emergence of new SARS-CoV-2 variants that feature increased transmission and immune escape, there is an urgent demand for a better vaccine design that will provide broader neutralizing efficacy. METHODS: We report an mRNA-based vaccine using an engineered "hybrid" receptor binding domain (RBD) that contains all 16 point-mutations shown in the currently prevailing Omicron and Delta variants. RESULTS: A booster dose of hybrid vaccine in mice previously immunized with wild-type RBD vaccine induced high titers of broadly neutralizing antibodies against all tested SARS-CoV-2 variants of concern (VOCs). In naïve mice, hybrid vaccine generated strong Omicron-specific neutralizing antibodies as well as low but significant titers against other VOCs. Hybrid vaccine also elicited CD8+/IFN-γ+ T cell responses against a conserved T cell epitope present in wild type and all VOCs. CONCLUSIONS: These results demonstrate that inclusion of different antigenic mutations from various SARS-CoV-2 variants is a feasible approach to develop cross-protective vaccines.

Comparison of short-term outcomes between totally laparoscopic right colectomy and laparoscopic-assisted right colectomy: a retrospective study in a single institution on 300 consecutive patients.

BACKGROUND: Laparoscopic surgery has become the standard surgical approach for the treatment of colon cancer. However, the surgical procedure for right colectomy is not standardized. Selection between laparoscopy-assisted right colectomy (LARC) with extracorporeal anastomosis and totally laparoscopic procedures with intracorporeal anastomosis is still a hot topic. The aim of this study was to compare the short-term outcomes of totally laparoscopic right colectomy (TLRC) and LARC in the treatment of right colon cancer. METHODS: This was a retrospective and single-center study conducted between January 2016 and December 2019 featuring 120 TLRC patients and 180 LARC patients following the principles of the CME. We then collated and analyzed the clinicopathological characteristics, operative characteristics, and short-term outcomes. RESULTS: The baseline characteristics were balanced between two groups. TLRC was associated with a significantly lower estimated blood loss (p < 0.01), a shorter incision length (p < 0.01). In terms of postoperative recovery, patients in TLRC group were better, as confirmed by less postoperative pain (p < 0.01), less rescue analgesic usage (p = 0.04), faster to flatus (p < 0.01), defecation (p < 0.01), oral intake (p < 0.01) and discharge (p < 0.01). Incidence of postoperative complications according to Clavien-Dindo classification system was also similar in both groups. CONCLUSIONS: Our data demonstrate that TLRC is technically safe and feasible. This technique could lead to a better cosmetic outcome, a less pain experience and a faster recovery of bowel function.

Does nail size or difference between canal and nail diameter influence likelihood of union or time to union of femoral shaft fractures treated with intramedullary nailing? A retrospective cohort study.

BACKGROUND: This study aims to determine whether nail size or the difference between canal and nail diameter (CN difference) affects the union rate and time of femoral shaft fracture treated with an interlocking intramedullary nail (IMN). METHODS: This was a retrospective review of 257 patients with femoral shaft fractures treated with IMN at a tertiary trauma medical center. All the IMN inserted were the same (Stryker T2 Femoral Nail). The patients were divided into groups based on nail size (10-, 11-, 12-, or 13-mm) and CN difference (< 1, 1-2, or > 2 mm), and union rate and time to union were compared. RESULTS: The 10-, 11-, 12-, and 13-mm groups based on nail size had 113, 74, 54, and 16 patients, respectively. The overall union rate was 97% (257/265). No significant differences in union rate or time to union were observed among these 4 groups. The groups based on CN differences of < 1-, 1 to 2, and > 2 mm comprised 143, 79, and 35 patients, respectively. Again, no significant differences were noted in union rate or mean time to union among the groups. CONCLUSIONS: Similar union rate and time to union were observed, regardless of nail size or CN difference. This finding indicates that most simple femoral shaft fractures can be treated with a standard, reamed 10-mm IMN. A larger nail insertion is unnecessary and presents more risks; comparatively, the use of a small nail with less reaming is simpler, requires shorter operative times, results in less blood loss, and is less expensive.