Impact of being underweight on peri-operative and post-operative outcomes of total knee or hip arthroplasty: A meta-analysis.

BACKGROUND: Many systematic reviews have focused on assessing the effect of body mass index (BMI) on the outcomes and complications associated with total hip arthroplasty (THA) and total knee arthroplasty (TKA), but primarily dealt with obesity compared to normal weight (NW). None of these reviews attempted to assess the effect of low BMI or underweight (UW) compared to NW in patients undergoing THA or TKA. AIM: This review aims to compare specific operative outcomes such as operation duration, length of hospital stay, and post-operative complications including mortality, infections, deep vein thrombosis, etc. along with re-hospitalization and reoperation rates between UW and NW patients undergoing THA, TKA or both. METHODS: An electronic search was performed in PubMed, Scopus, Excerpta Medica database (EMBASE), Web of Science (WoS), and Cochrane Central Register of Controlled Trials (CENTRAL) along with a manual search. The quality of the studies was assessed using the Newcastle-Ottawa scale for cohort studies. The data were subjected to both qualitative and quantitative analysis. RESULTS: Thirteen retrospective and five prospective cohort studies were included. The quality of included studies was assessed to be good to fair. The length of hospital stay after TKA or THA was found to be significantly higher for UW patients when compared to NW patients, with a mean difference: 0.39 95%CI: [0.06, 0.72], P = 0.02 (in days). Studies presenting both THA and TKA together as total joint arthroplasty showed an increased incidence of mortality in patients treated with THA or TKA alone, Odds ratio: 4.18 95%CI: [2.88, 6.07]. A higher incidence of post-operative complications was also observed in UW patients undergoing THA. CONCLUSION: UW patients undergoing THA or TKA had a higher incidence of post-operative complications and were associated with a higher readmission rate. Moreover, UW patients were associated with an increased incidence of mortality in the studies that reported THA and TKA together.

Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies.

The highly mutated and transmissible Omicron (BA.1) and its more contagious lineage BA.2 have provoked serious concerns over their decreased sensitivity to the current COVID-19 vaccines and evasion from most anti-SARS-CoV-2 neutralizing antibodies (NAbs). In this study, we explored the possibility of combating the Omicron and BA.2 by constructing bispecific antibodies based on non-Omicron NAbs. We engineered 10 IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, 8 out of 10 bispecific antibodies showed high binding affinities to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron and BA.2, with geometric mean of 50% inhibitory concentration (GM IC50) values ranging from 4.5 ng/mL to 103.94 ng/mL, as well as the authentic BA.1.1. Six bispecific antibodies containing the cross-NAb GW01 not only neutralized Omicron and BA.2, but also neutralized the sarbecoviruses including SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) RS3367 and WIV1, with GM IC50 ranging from 11.6 ng/mL to 103.9 ng/mL. Mapping analyses of 42 spike (S) variant single mutants of Omicron and BA.2 elucidated that these bispecific antibodies accommodated the S371L/F mutations, which were resistant to most of the non-Omicron NAbs. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody GW01-16L9 (FD01) in its native full-length IgG form in complex with the Omicron S trimer revealed 5 distinct trimers and one novel trimer dimer conformation. 16L9 scFv binds the receptor-binding motif (RBM), while GW01 scFv binds a epitope outside the RBM. Two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3 RBD-up conformation, improved the affinity between IgG and the Omicron RBD, induced the formation of trimer dimer, and inhibited RBD binding to ACE2. The trimer dimer conformation might induce the aggregation of virions and contribute to the neutralization ability of FD01. These novel bispecific antibodies are strong candidates for the treatment and prevention of infection with the Omicron, BA.2, VOCs, and other sarbecoviruses. Engineering bispecific antibodies based on non-Omicron NAbs could turn the majority of NAbs into a powerful arsenal to aid the battle against the pandemic.

Impact of diabetes mellitus on risk of major complications after hip fracture: a systematic review and meta-analysis.

BACKGROUND: The impact of diabetes mellitus (DM) on adverse outcomes in hip fracture patients is unclear. Furthermore, no review has synthesized evidence on this subject. Therefore, the current study was designed to answer the following research question: Does DM increase the risk of mortality and major systemic complications in patients with hip fractures? METHODS: PubMed, Embase, and Google Scholar were searched from 1st January 2000 to 1st August 2021 for studies comparing DM and non-DM patients with hip fractures. Outcomes of interest were pooled using risk ratios (RR). The study was registered on PROSPERO (CRD42021268525). RESULTS: Sixteen studies were included. Meta-analysis revealed a statistically significant increased risk of mortality in diabetics as compared to non-diabetics after 1 year (RR: 1.24 95% CI 1.08, 1.43 I2 = 62% p = 0.003). Pooled analysis of eight studies reporting adjusted mortality outcomes also demonstrated similar results (RR: 1.17 95% CI 1.09, 1.25 I2 = 74% p < 0.0001). We noted a statistically significant increase in the risk of cardiac complications (RR: 1.44 95% CI 1.17, 1.78 I2 = 19% p = 0.0005) and risk of renal failure in diabetics as compared to non-diabetics (RR: 1.32 95% CI 1.04, 1.68 I2 = 0% p = 0.02); but no difference in the risk of cerebrovascular (RR: 1.45 95% CI 0.74, 2.85 I2 = 47% p = 0.28), pulmonary (RR: 0.94 95% CI 0.73, 1.23 I2 = 8% p = 0.67) and thromboembolic complications (RR: 0.81 95% CI 0.56, 1.17 I2 = 28% p = 0.26). CONCLUSION: Our results indicate that diabetics have an increased risk of mortality as compared to non-diabetics. Scarce data indicates that the risk of cardiac complications and renal failure are increased in patients with DM but there is no difference in the risk of cerebrovascular, pulmonary, or thromboembolic complications. Further studies are needed to strengthen the current conclusions.

Novel sarbecovirus bispecific neutralizing antibodies with exceptional breadth and potency against currently circulating SARS-CoV-2 variants and sarbecoviruses.

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) has aroused concerns over their increased infectivity and transmissibility, as well as decreased sensitivity to SARS-CoV-2-neutralizing antibodies (NAbs) and the current coronavirus disease 2019 (COVID-19) vaccines. Such exigencies call for the development of pan-sarbecovirus vaccines or inhibitors to combat the circulating SARS-CoV-2 NAb-escape variants and other sarbecoviruses. In this study, we isolated a broadly NAb against sarbecoviruses named GW01 from a donor who recovered from COVID-19. Cryo-EM structure and competition assay revealed that GW01 targets a highly conserved epitope in a wide spectrum of different sarbecoviruses. However, we found that GW01, the well-known sarbecovirus NAb S309, and the potent SARS-CoV-2 NAbs CC12.1 and REGN10989 only neutralize about 90% of the 56 tested currently circulating variants of SARS-CoV-2 including Omicron. Therefore, to improve efficacy, we engineered an IgG-like bispecific antibody GW01-REGN10989 (G9) consisting of single-chain antibody fragments (scFv) of GW01 and REGN10989. We found that G9 could neutralize 100% of NAb-escape mutants (23 out of 23), including Omicron variant, with a geometric mean (GM) 50% inhibitory concentration of 8.8 ng/mL. G9 showed prophylactic and therapeutic effects against SARS-CoV-2 infection of both the lung and brain in hACE2-transgenic mice. Site-directed mutagenesis analyses revealed that GW01 and REGN10989 bind to the receptor-binding domain in different epitopes and from different directions. Since G9 targets the epitopes for both GW01 and REGN10989, it was effective against variants with resistance to GW01 or REGN10989 alone and other NAb-escape variants. Therefore, this novel bispecific antibody, G9, is a strong candidate for the treatment and prevention of infection by SARS-CoV-2, NAb-escape variants, and other sarbecoviruses that may cause future emerging or re-emerging coronavirus diseases.

GADD45G Interacts with E-cadherin to Suppress the Migration and Invasion of Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIMS: Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers with poor prognosis. Metastasis is the leading cause of cancer-related deaths. The growth arrest and DNA damage-inducible 45 gamma (GADD45G) has been reported to correlate with survival, invasion, and metastasis of ESCC. This study was aimed to investigate the role and mechanism of GADD45G in ESCC cell migration and invasion. METHODS: Both the effects of GADD45G and its need for E-cadherin to function on ESCC cell migration and invasion were determined through loss- and gain-of-function approaches via Transwell assays. The interaction between GADD45G and E-cadherin was detected by GST-pull down and IP assays. The expression of E-cadherin upon GADD45G overexpression was evaluated by RT-qPCR and western blot. The level of E-cadherin in cytoplasmic, nuclear, and membrane fractions was examined by western blot following subcellular fractionation. RESULTS: Knockdown of GADD45G increased the migration and invasion abilities of KYSE150 cells, while overexpression of GADD45G showed the opposite effects on YES2 and KYSE30 cells. GADD45G could interact with E-cadherin and enhanced its membrane level. Knockdown of E-cadherin abolished the inhibitory effects of GADD45G on ESCC cell migration and invasion. Intriguingly, dimer-dissociating mutant of GADD45G could not interact with E-cadherin and almost lost its ability to suppress the ESCC cell migration and invasion. CONCLUSIONS: This study reveals a novel role for GADD45G in inhibiting the ESCC cell migration and invasion, which will provide a new insight in understanding the ESCC metastatic mechanism.

FAT1, a direct transcriptional target of E2F1, suppresses cell proliferation, migration and invasion in esophageal squamous cell carcinoma.

OBJECTIVE: Growing evidence indicates that FAT atypical cadherin 1 (FAT1) has aberrant genetic alterations and exhibits potential tumor suppressive function in esophageal squamous cell carcinoma (ESCC). However, the role of FAT1 in ESCC tumorigenesis remains not well elucidated. The aim of this study was to further investigate genetic alterations and biological functions of FAT1, as well as to explore its transcriptional regulation and downstream targets in ESCC. METHODS: The mutations of FAT1 in ESCC were achieved by analyzing a combined study from seven published genomic data, while the copy number variants of FAT1 were obtained from an analysis of our previous data as well as of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases using the cBioPortal. The transcriptional regulation of FAT1 expression was investigated by chromatin immunoprecipitation (ChIP) and the luciferase reporter assays. In-cell western, Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to assess the indicated gene expression. In addition, colony formation and Transwell migration/invasion assays were employed to test cell proliferation, migration and invasion. Finally, RNA sequencing was used to study the transcriptomes. RESULTS: FAT1 was frequently mutated in ESCC and was deleted in multiple cancers. Furthermore, the transcription factor E2F1 occupied the promoter region of FAT1, and depletion of E2F1 led to a decrease in transcription activity and mRNA levels of FAT1. Moreover, we found that knockdown of FAT1 promoted KYSE30 and KYSE150 cell proliferation, migration and invasion; while overexpression of FAT1 inhibited KYSE30 and KYSE410 cell proliferation, migration and invasion. In addition, knockdown of FAT1 led to enrichment of the mitogen-activated protein kinase (MAPK) signaling pathway and cell adhesion process. CONCLUSIONS: Our data provided evidence for the tumor suppressive function of FAT1 in ESCC cells and elucidated the transcriptional regulation of FAT1 by E2F1, which may facilitate the understanding of molecular mechanisms of the progression of ESCC.

Long noncoding RNA PCAT1, a novel serum-based biomarker, enhances cell growth by sponging miR-326 in oesophageal squamous cell carcinoma.

Long noncoding RNAs (lncRNAs) play important roles in the development and progression of human cancers. The lncRNA prostate cancer-associated transcript 1 (PCAT1) has been reported to be involved in multiple human cancers, including oesophageal squamous cell carcinoma (ESCC). However, the detailed biological functions, underlying mechanisms and clinical relevance of PCAT1 in ESCC remain unclear. Here, we confirmed that PCAT1 was highly expressed in ESCC tissues and cell lines. Knockdown of PCAT1 inhibited the growth of ESCC cells, whereas overexpression of PCAT1 showed the opposite effect both in vitro and in vivo. Moreover, knockdown of PCAT1 arrested the cell cycle at G2/M phase, reduced the expression of cyclin B1 and CDC2, and caused cells to be more sensitive to paclitaxel. Furthermore, PCAT1 could bind to miR-326, a tumour suppressor in diverse human cancers. Rescue experiments revealed that enforced expression of miR-326 attenuated the promotive effect of PCAT1 on ESCC cell growth. In addition, we discovered that PCAT1 was present in ESCC cell-derived exosomes, was higher in the serum of ESCC patients than those of healthy volunteer donors, and promoted cell growth through exosomes. Thus, our data indicate that PCAT1 promotes ESCC cell proliferation by sponging miR-326 and may serve as a non-invasive biomarker for ESCC.

All-Inorganic CsPbI2Br Perovskite Solar Cells with High Efficiency Exceeding 13.

All-inorganic perovskite solar cells provide a promising solution to tackle the thermal instability problem of organic-inorganic perovskite solar cells (PSCs). Herein, we designed an all-inorganic perovskite solar cell with novel structure (FTO/NiO x/CsPbI2Br/ZnO@C60/Ag), in which ZnO@C60 bilayer was utilized as the electron-transporting layers that demonstrated high carrier extraction efficiency and low leakage loss. Consequently, the as-fabricated all-inorganic CsPbI2Br perovskite solar cell yielded a power conversion efficiency (PCE) as high as 13.3% with a Voc of 1.14 V, Jsc of 15.2 mA·cm-2, and FF of 0.77. The corresponding stabilized power output (SPO) of the device was demonstrated to be ∼12% and remarkably stable within 1000 s. Importantly, the obtained all-inorganic PSCs without encapsulation exhibited only 20% PCE loss with thermal treatment at 85 °C for 360 h, which largely outperformed the organic-species-containing PSCs. The present study demonstrates potential in overcoming the intractable issue concerning the thermal instability of perovskite solar cells.