One-Step Intraoperative Optical Coherence Tomography Guided Tunnel, Mushroom Femtosecond Laser Big Bubble Deep Anterior Lamellar Keratoplasty.

The aim of our study is to investigate the feasibility and outcomes of using a femtosecond laser (FSL) platform (Ziemer LDV Z8) for deep anterior lamellar keratoplasty (DALK), enabling the creation of mushroom-shaped graft-host junctions, lamellar cuts, and intrastromal tunnels, to facilitate the big bubble, in one step. We included wet lab experiments on nine porcine eyes to assess the laser accuracy and cuts depth using an anterior segment (AS) OCT. This was followed by an interventional prospective case series on 10 eyes with variant corneal pathologies. The Z8 system, with in-built intraoperative optical coherence tomography (iOCT), guided corneal scans and directed the cuts. ASOCT showed visible mushroom configurations, lamellar cuts, and tunnels. Deviations from the target were 1.6%, 2.6%, and 3.5%. Anterior lamellar removal was easy in all clinical cases, including corneal scarring. The intrastromal tunnel was found at the preset location and the mushroom configuration was acquired. A big bubble was achieved in all cases. Type 1, 2, and 3 bubbles were formed in eight, one, and one case, respectively. We describe a new approach to DALK in which the in-built iOCT-guided FSL enables safe, precise, controlled, and reproducible desired cuts in one step. The preliminary clinical outcomes were favorable.

High-density lipoprotein cholesterol abnormalities correlate with severe fatigue in major depressive disorder: A cross-sectional study.

OBJECTIVES: This cross-sectional study aimed to characterize the differences of metabolic profiles and atherogenicity between various levels of fatigue severity in patients with major depressive disorder (MDD), and examine the extent to which metabolic abnormality correlates with fatigue severity. METHODS: We recruited 119 patients with MDD and assessed fatigue severity using Krupp's Fatigue Severity Scale. Blood samples were collected to determine plasma levels of fasting glucose, high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol and low-density lipoprotein cholesterol. The atherogenic index of plasma (AIP) was calculated as log10 (triglycerides/HDL-C). RESULTS: MDD with severe fatigue were more likely to be younger (43.3 ± 10.3 years vs. 49.4 ± 8.5 years, p = 0.001), had a younger age of onset (34.7 ± 9.7 years vs. 40.7 ± 9.5 years, p = 0.001), demonstrated higher HAMD scores (18.0 ± 7.6 vs. 10.9 ± 7.5, p < 0.001), as well as lower HDL-C levels (48.5 ± 10.8 vs. 55.3 ± 13.9, p = 0.003), a greater prevalence of low HDL-C (43.9% vs. 22.6%, p = 0.015) and higher AIP levels (0.4 ± 0.3 vs. 0.3 ± 0.3, p = 0.046). Both a decreased plasma HDL-C level (OR = 0.95, 95% CI = 0.91-0.99, p = 0.009) and a diagnosis of low HDL-C (OR = 3.29, 95% CI = 1.27-8.57, p = 0.015) were significantly correlated with an increased risk of fatigue severity. CONCLUSION: HDL-C could potentially protect patients with MDD from severe fatigue and the associated risk of cardiovascular disease.

Potential therapeutic effects of peroxisome proliferator-activated receptors on corneal diseases.

The cornea is an avascular tissue in the eye that has multiple functions in the eye to maintain clear vision which can significantly impair one's vision when subjected to damage. Peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptor proteins comprising three different peroxisome proliferator-activated receptor (PPAR) isoforms, namely, PPAR alpha (α), PPAR gamma (γ), and PPAR delta (δ), have emerged as potential therapeutic targets for treating corneal diseases. In this review, we summarised the current literature on the therapeutic effects of PPAR agents on corneal diseases. We discussed the role of PPARs in the modulation of corneal wound healing, suppression of corneal inflammation, neovascularisation, fibrosis, stimulation of corneal nerve regeneration, and amelioration of dry eye by inhibiting oxidative stress within the cornea. We also discussed the underlying mechanisms of these therapeutic effects. Future clinical trials are warranted to further attest to the clinical therapeutic efficacy.

Tailoring parameters for QM/MM simulations: accurate modeling of adsorption and catalysis in zirconium-based metal-organic frameworks.

Quantum mechanics/molecular mechanics (QM/MM) simulations offer an efficient way to model reactions occurring in complex environments. This study introduces a specialized set of charge and Lennard-Jones parameters tailored for electrostatically embedded QM/MM calculations, aiming to accurately model both adsorption processes and catalytic reactions in zirconium-based metal-organic frameworks (Zr-MOFs). To validate our approach, we compare adsorption energies derived from QM/MM simulations against experimental results and Monte Carlo simulation outcomes. The developed parameters showcase the ability of QM/MM simulations to represent long-range electrostatic and van der Waals interactions faithfully. This capability is evidenced by the prediction of adsorption energies with a low root mean square error of 1.1 kcal mol-1 across a wide range of adsorbates. The practical applicability of our QM/MM model is further illustrated through the study of glucose isomerization and epimerization reactions catalyzed by two structurally distinct Zr-MOF catalysts, UiO-66 and MOF-808. Our QM/MM calculations closely align with experimental activation energies. Importantly, the parameter set introduced here is compatible with the widely used universal force field (UFF). Moreover, we thoroughly explore how the size of the cluster model and the choice of density functional theory (DFT) methodologies influence the simulation outcomes. This work provides an accurate and computationally efficient framework for modeling complex catalytic reactions within Zr-MOFs, contributing valuable insights into their mechanistic behaviors and facilitating further advancements in this dynamic area of research.

Integrating In Silico and In Vitro Approaches to Identify Natural Peptides with Selective Cytotoxicity against Cancer Cells.

Anticancer peptides (ACPs) are bioactive compounds known for their selective cytotoxicity against tumor cells via various mechanisms. Recent studies have demonstrated that in silico machine learning methods are effective in predicting peptides with anticancer activity. In this study, we collected and analyzed over a thousand experimentally verified ACPs, specifically targeting peptides derived from natural sources. We developed a precise prediction model based on their sequence and structural features, and the model's evaluation results suggest its strong predictive ability for anticancer activity. To enhance reliability, we integrated the results of this model with those from other available methods. In total, we identified 176 potential ACPs, some of which were synthesized and further evaluated using the MTT colorimetric assay. All of these putative ACPs exhibited significant anticancer effects and selective cytotoxicity against specific tumor cells. In summary, we present a strategy for identifying and characterizing natural peptides with selective cytotoxicity against cancer cells, which could serve as novel therapeutic agents. Our prediction model can effectively screen new molecules for potential anticancer activity, and the results from in vitro experiments provide compelling evidence of the candidates' anticancer effects and selective cytotoxicity.

The effects of mindful exercise on cognition in patients with schizophrenia: A systematic review and meta-analysis of randomized controlled trials.

Cognitive impairment is a core symptom of schizophrenia. This study investigated the effects of mindful exercise on the cognitive performance of individuals with schizophrenia. A systematic review and meta-analysis were performed from inception to March 2023. The quality of included studies was evaluated using the Physiotherapy Evidence Database (PEDro) scale. A random effects model was used to generate the pooled effect size. Ten randomized controlled trials met the inclusion criteria with fair-to-good methodological quality. The results showed that Mindful exercise significantly improved global cognition in patients with schizophrenia (g = 0.25, p = .002). There was a significant difference in mindful exercise compared with the passive control group (g = 0.34, p = .002), whereas no significant difference was found between the mindful exercise and exercise intervention group (g = 0.09, p = .371). These findings indicate that mindful exercise could be promising for improving cognition in patients with schizophrenia.

Effectiveness of high-intensity focused ultrasound combined with gonadotropin-releasing hormone agonist or combined with levonorgestrel-releasing intrauterine system for adenomyosis: A systematic review and meta-analysis.

Gonadotropin-Releasing Hormone Agonist (GnRH-a) and levonorgestrel releasing intrauterine system (LNG-IUS) are conventional conservative treatments for adenomyosis, and high-intensity focused ultrasound (HIFU) is a novel ablation technique. This study aimed to investigate the effectiveness of HIFU combined with GnRH-a or LNG-IUS for adenomyosis patients. In this systematic review and meta-analysis, Pubmed, Embase, Cochrane Library and Scopus databases were searched up to December 2021. Published studies comparing HIFU plus GnRH-a with HIFU plus LNG-IUS in adenomyosis patients were assessed for eligibility by two independent authors. Risk of bias tool was utilized for risk evaluation. We selected treatment effective rate of dysmenorrhea (pain during menstruation) as the primary outcome; effective rate of menorrhagia severity and reduction rate of adenomyotic lesion as the secondary outcomes. Adverse effects were assessed. Four studies with a total 729 patients were enrolled in the meta-analysis. HIFU plus LNG-IUS showed lower dysmenorrhea [within 6 months: risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83-0.93, p < 0.00001; over 1 year: RR 0.73, 95% CI 0.65-0.82, p < 0.00001] and less menorrhagia severity (RR 0.63, 95% CI 0.60-0.66, p < 0.00001) than HIFU plus GnRH-a. Both groups demonstrated equal efficacy in adenomyotic lesion reduction rate (RR 1.03, 95% CI 0.97-1.09, p = 0.30). Adverse effects happened equally in both groups. Combination therapy of HIFU and LNG-IUS revealed better effectiveness in treating dysmenorrhea and menorrhagia than that of HIFU and GnRH-a. However, interpreting the conclusion should be approached with caution as a result of significant heterogeneity.

Multi-modality imaging parameters that predict rapid tumor regression in head and neck radiotherapy.

Background and purpose: Volume regression during radiotherapy can indicate patient-specific treatment response. We aimed to identify pre-treatment multimodality imaging (MMI) metrics from positron emission tomography (PET), magnetic resonance imaging (MRI), and computed tomography (CT) that predict rapid tumor regression during radiotherapy in human papilloma virus (HPV) associated oropharyngeal carcinoma. Materials and methods: Pre-treatment FDG PET-CT, diffusion-weighted MRI (DW-MRI), and intra-treatment (at 1, 2, and 3 weeks) MRI were acquired in 72 patients undergoing chemoradiation therapy for HPV+ oropharyngeal carcinoma. Nodal gross tumor volumes were delineated on longitudinal images to measure intra-treatment volume changes. Pre-treatment PET standardized uptake value (SUV), CT Hounsfield Unit (HU), and non-gaussian intravoxel incoherent motion DW-MRI metrics were computed and correlated with volume changes. Intercorrelations between MMI metrics were also assessed using network analysis. Validation was carried out on a separate cohort (N = 64) for FDG PET-CT. Results: Significant correlations with volume loss were observed for baseline FDG SUVmean (Spearman ρ = 0.46, p < 0.001), CT HUmean (ρ = 0.38, p = 0.001), and DW-MRI diffusion coefficient, Dmean (ρ = -0.39, p < 0.001). Network analysis revealed 41 intercorrelations between MMI and volume loss metrics, but SUVmean remained a statistically significant predictor of volume loss in multivariate linear regression (p = 0.01). Significant correlations were also observed for SUVmean in the validation cohort in both primary (ρ = 0.30, p = 0.02) and nodal (ρ = 0.31, p = 0.02) tumors. Conclusions: Multiple pre-treatment imaging metrics were correlated with rapid nodal gross tumor volume loss during radiotherapy. FDG-PET SUV in particular exhibited significant correlations with volume regression across the two cohorts and in multivariate analysis.

Integrative genomics identifies SHPRH as a tumor suppressor gene in lung adenocarcinoma that regulates DNA damage response.

BACKGROUND: Identification of driver mutations and development of targeted therapies has considerably improved outcomes for lung cancer patients. However, significant limitations remain with the lack of identified drivers in a large subset of patients. Here, we aimed to assess the genomic landscape of lung adenocarcinomas (LUADs) from individuals without a history of tobacco use to reveal new genetic drivers of lung cancer. METHODS: Integrative genomic analyses combining whole-exome sequencing, copy number, and mutational information for 83 LUAD tumors was performed and validated using external datasets to identify genetic variants with a predicted functional consequence and assess association with clinical outcomes. LUAD cell lines with alteration of identified candidates were used to functionally characterize tumor suppressive potential using a conditional expression system both in vitro and in vivo. RESULTS: We identified 21 genes with evidence of positive selection, including 12 novel candidates that have yet to be characterized in LUAD. In particular, SNF2 Histone Linker PHD RING Helicase (SHPRH) was identified due to its frequency of biallelic disruption and location within the familial susceptibility locus on chromosome arm 6q. We found that low SHPRH mRNA expression is associated with poor survival outcomes in LUAD patients. Furthermore, we showed that re-expression of SHPRH in LUAD cell lines with inactivating alterations for SHPRH reduces their in vitro colony formation and tumor burden in vivo. Finally, we explored the biological pathways associated SHPRH inactivation and found an association with the tolerance of LUAD cells to DNA damage. CONCLUSIONS: These data suggest that SHPRH is a tumor suppressor gene in LUAD, whereby its expression is associated with more favorable patient outcomes, reduced tumor and mutational burden, and may serve as a predictor of response to DNA damage. Thus, further exploration into the role of SHPRH in LUAD development may make it a valuable biomarker for predicting LUAD risk and prognosis.

Partial fixed dental prostheses fabricated using fiber-reinforced composite resin supported by short and extra-short implants: A case series.

PURPOSE: This study aimed to evaluate the 10-year outcomes of partial fixed dental prostheses (P-FDPs) fabricated using metal-free fiber-reinforced composite (FRC) resin frameworks veneered with composite resin and supported by short and extra-short implants. METHODS: This study included 28 patients with 38 FRC prostheses supported by 96 implants. Implant and prosthesis survival and success rates were evaluated using Kaplan-Meier analysis. RESULTS: The 10-year implant survival and success rate, as determined by Kaplan-Meier analysis, was 96.9%, and the prosthesis survival and success rates were 94.7% and 92.0%, respectively. None of the parameters under investigation were significantly correlated with prosthetic survival or successful outcomes, but three parameters were correlated with higher peri-implant bone levels: implant placement in the mandible as opposed to the maxilla, shorter P-FDP spans, and natural teeth on the opposing arch. CONCLUSIONS: FRC P-FDPs supported by short and extra-short implants presented high, up to 10-year, survival and success rates, when used to restore partially edentulous arches.

Understanding REM Sleep Behavior Disorder through Functional MRI: A Systematic Review.

Neuroimaging studies in rapid eye movement sleep behavior disorder (RBD) can inform fundamental questions about the pathogenesis of Parkinson's disease (PD). Across modalities, functional magnetic resonance imaging (fMRI) may be better suited to identify changes between neural networks in the earliest stages of Lewy body diseases when structural changes may be subtle or absent. This review synthesizes the findings from all fMRI studies of RBD to gain further insight into the pathophysiology and progression of Lewy body diseases. A total of 32 studies were identified using a systematic review conducted according to PRISMA guidelines between January 2000 to February 2024 for original fMRI studies in patients with either isolated RBD (iRBD) or RBD secondary to PD. Common functional alterations were detectable in iRBD patients compared with healthy controls across brainstem nuclei, basal ganglia, frontal and occipital lobes, and whole brain network measures. Patients with established PD and RBD demonstrated decreased functional connectivity across the whole brain and brainstem nuclei, but increased functional connectivity in the cerebellum and frontal lobe compared with those PD patients without RBD. Finally, longitudinal changes in resting state functional connectivity were found to track with disease progression. Currently, fMRI studies in RBD have demonstrated early signatures of neurodegeneration across both motor and non-motor pathways. Although more work is needed, such findings have the potential to inform our understanding of disease, help to distinguish between prodromal PD and prodromal dementia with Lewy bodies, and support the development of fMRI-based outcome measures of phenoconversion and progression in future disease modifying trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neutrophil-to-lymphocyte ratio as a predictor for outcomes in patients with short-term emergency department revisits.

BACKGROUND: Analysis of short-term emergency department (ED) revisits is a common emergency care quality assurance practice. Previous studies have explored various risk factors of ED revisits; however, laboratory data were usually omitted. This study aimed to evaluate the prognostic significance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte (PLR), and systemic immune-inflammation index (SII) in predicting outcomes of patients revisiting the ED. METHODS: This retrospective observational cohort study investigated short-term ED revisit patients. The primary outcome measure was high-risk ED revisit, a composite of in-hospital mortality or intensive care unit (ICU) admission after 72-h ED revisit. The NLR, PLR, and SII were investigated as potential prognostic predictors of ED revisit outcomes. RESULTS: A total of 1916 encounters with short-term ED revisit patients were included in the study; among these, 132 (6.9%) encounters, comprising 57 in-hospital mortalities and 95 ICU admissions, were high-risk revisits. High-risk revisit patients had significantly higher NLR, PLR, and SII (11.6 vs. 6.6, p<0.001; 26.2 vs. 18.9, p=0.004; 2209 vs. 1486, p=0.002, respectively). Multiple regression analysis revealed revisit-NLR as an independent factor for predicting poor outcomes post-ED revisits (Odds Ratio: 1.031, 95% Confidence Interval: 1.017-1.045, p<0.001); an optimal cut-off value of 7.9 was proven for predicting high-risk ED revisit. CONCLUSION: The intensity of the inflammatory response expressed by NLR was an independent predictor for poor outcomes of ED revisits and should be considered when ED revisits occur. Future prediction models for ED revisit outcomes can include revisit-NLR as a potential predictor to reflect the progressive conditions in ED patients.

Simplified Fabrication of a Lingual Splint for Management of Mandibular Fractures.

Lingual splints have been used to treat mandibular fractures, particularly in cases of complicated mandibular fractures, and serve as a noninvasive adjunctive procedure for reduction and fixation. Furthermore, when used in conjunction with open reduction and internal fixation, the lingual splint provides feasible external fixation against displacing forces exerted by the robust musculature of the mandible. However, the conventional method for lingual splint fabrication is performed preoperatively, and the procedure is time-consuming. This technical note describes a simplified and efficient technique for the intraoperative manufacture of a lingual splint for mandibular fractures using a thermoplastic material, polycaprolactone. Our results demonstrated satisfactory fixation outcomes, reduced lingual splint fabrication time, and superior cost-effectiveness, offering an alternative option for adjunctive external fixation of mandibular fractures.

Topical and oral peroxisome proliferator-activated receptor-α agonist ameliorates diabetic corneal neuropathy.

Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal ß-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased ß-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation.

Lexical Morphology as a Source of Risk and Resilience for Learning to Read With Dyslexia: An fNIRS Investigation.

PURPOSE: We examined the neurocognitive bases of lexical morphology in children of varied reading abilities to understand the role of meaning-based skills in learning to read with dyslexia. METHOD: Children completed auditory morphological and phonological awareness tasks during functional near-infrared spectroscopy neuroimaging. We first examined the relation between lexical morphology and phonological processes in typically developing readers (Study 1, N = 66, Mage = 8.39), followed by a more focal inquiry into lexical morphology processes in dyslexia (Study 2, N = 50, Mage = 8.62). RESULTS: Typical readers exhibited stronger engagement of language neurocircuitry during the morphology task relative to the phonology task, suggesting that morphological analyses involve synthesizing multiple components of sublexical processing. This effect was stronger for more analytically complex derivational affixes (like + ly) than more semantically transparent free base morphemes (snow + man). In contrast, children with dyslexia exhibited stronger activation during the free base condition relative to derivational affix condition. Taken together, the findings suggest that although children with dyslexia may struggle with derivational morphology, they may also use free base morphemes' semantic information to boost word recognition. CONCLUSION: This study informs literacy theories by identifying an interaction between reading ability, word structure, and how the developing brain learns to recognize words in speech and print. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25944949.

Hypervitaminosis D is correlated with adverse dental implant outcomes: A retrospective case-control study.

OBJECTIVES: To investigate vitamin-D levels effect on the survival/success and on marginal bone levels of dental implants. METHODS: Patients with peri-implant disease and healthy control patients with functionally loaded dental implants were included in this retrospective case-control study. Forty patients with 201 implants were in the diseased-cohort, while thirty-three patients with 90 implants were in the control-cohort. Patient blood 25(OH)D levels were assessed through quantitative blood test. The correlation between abnormal 25(OH)D levels and disease status of each patient was assessed using Fisher's exact tests. The correlation of each implant's outcomes with vitamin-D status was assessed using Kaplan-Meier survival analysis and Mann-Whitney U tests. RESULTS: Patients with blood 25(OH)D levels >70 ng/mL (hypervitaminosis-D) had a 21.1-fold increase in the risk of implant failure or severe peri-implant bone loss regarding patients with intermediate (>30, ≤70 ng/mL) levels. Kaplan-Meier survival analysis revealed that implants in the hypervitaminosis-D cohort had a survival probability of 73.7 % (95 % CI:56.5-84.5 %) at 19-years after surgery, compared to 95 % for implants in patients with intermediate 25(OH)D levels (95 % CI:88.3-97.9 %). Additionally, implants in the hypervitaminosis-D cohort lost bone faster than implants in the intermediate cohort. These results were specific to the patient cohort with elevated blood 25(OH)D levels and not observed in patients taking vitamin-D supplementation. The impact of hypervitaminosis-D was enriched for implants in the maxilla, and not as apparent for implants in the mandible. CONCLUSIONS: Blood 25(OH)D levels >70 ng/mL were correlated with adverse implant outcomes, including implant failure and peri-implant bone loss, especially in the maxilla. CLINICAL RELEVANCE: These results suggest that hypervitaminosis D may be a previously unidentified risk factor for dental implant complications and should be further investigated to elucidate the underlying mechanism.

Effects of Kinesiotaping on upper limb function and daily activities in subacute or chronic stroke survivors: A randomized control study.

BACKGROUND: Impaired upper limb function in stroke survivors is characterized by muscle weakness, increased muscle tone, contracture, or impaired motor control. OBJECTIVE: We aimed to evaluate the effectiveness of Kinesio-taping application for functional recovery on the affected arm and forearm during rehabilitation. METHODS: Forty-one patients eligible for this study were randomly assigned to either the Kinesio-taping group (n = 21), receiving Kinesio-taping intervention and conventional therapy, or control group (n = 20), receiving sham Kinesio-taping intervention and conventional therapy. The whole intervention lasted for 3 weeks. Fugl-Meyer assessment of the upper extremity, Barthel Index, the Stroke Impact Scale, and modified Ashworth scale were measured at 3 time points: baseline, post-treatment (3rd week), and follow-up (6th week). RESULTS: In the Kinesio-taping group, there were significant differences in the upper extremity (p = 0.003), wrist (p = 0.000) and hand (p = 0.000) parts of the Fugl-Meyer assessment of the upper extremity between the three assessment times. On the other hand, the Barthel Index showed significant differences in both groups after therapy. CONCLUSION: Combining conventional rehabilitation with Kinesio-taping intervention may improve functional motor performance of both the proximal and distal parts of the affected upper extremity in stroke survivors, with potential benefits for activity of daily living.

The presence of broadly neutralizing anti-SARS-CoV-2 RBD antibodies elicited by primary series and booster dose of COVID-19 vaccine.

Antibody-mediated immunity plays a key role in protection against SARS-CoV-2. We characterized B-cell-derived anti-SARS-CoV-2 RBD antibody repertoires from vaccinated and infected individuals and elucidate the mechanism of action of broadly neutralizing antibodies and dissect antibodies at the epitope level. The breadth and clonality of anti-RBD B cell response varies among individuals. The majority of neutralizing antibody clones lose or exhibit reduced activities against Beta, Delta, and Omicron variants. Nevertheless, a portion of anti-RBD antibody clones that develops after a primary series or booster dose of COVID-19 vaccination exhibit broad neutralization against emerging Omicron BA.2, BA.4, BA.5, BQ.1.1, XBB.1.5 and XBB.1.16 variants. These broadly neutralizing antibodies share genetic features including a conserved usage of the IGHV3-53 and 3-9 genes and recognize three clustered epitopes of the RBD, including epitopes that partially overlap the classically defined set identified early in the pandemic. The Fab-RBD crystal and Fab-Spike complex structures corroborate the epitope grouping of antibodies and reveal the detailed binding mode of broadly neutralizing antibodies. Structure-guided mutagenesis improves binding and neutralization potency of antibody with Omicron variants via a single amino-substitution. Together, these results provide an immunological basis for partial protection against severe COVID-19 by the ancestral strain-based vaccine and indicate guidance for next generation monoclonal antibody development and vaccine design.

Effectiveness of Adaptive Support Ventilation in Facilitating Weaning from Mechanical Ventilation in Postoperative Patients.

OBJECTIVE: This meta-analysis aims to evaluate the effectiveness of adaptive support ventilation (ASV) in facilitating postoperative weaning from mechanical ventilation in cardiac surgery patients. DESIGN: A systematic review and meta-analysis to assess ASV in weaning postoperative cardiac surgery patients. Outcomes included early extubation, reintubation rates, time to extubation, and lengths of intensive care units and hospital stays. SETTING: We searched electronic databases from inception to March 2023 and included randomized controlled trials that compared ASV with conventional ventilation methods in this population. PARTICIPANTS: Postoperative cardiac surgery patients. MEASUREMENTS AND MAIN RESULTS: A random effects model was used for meta-analysis, and trial sequential analysis (TSA) was conducted to assess result robustness. The meta-analysis included 11 randomized controlled trials with a total of 1027 randomized patients. ASV was associated with a shorter time to extubation compared to conventional ventilation (random effects, mean difference -68.30 hours; 95% confidence interval, -115.50 to -21.09) with TSA providing a conclusive finding. While ASV indicated improved early extubation rates, no significant differences were found in reintubation rates or lengths of intensive care unit and hospital stays, with these TSA results being inclusive. CONCLUSIONS: ASV appears to facilitate a shorter time to extubation in postoperative cardiac surgery patients compared to conventional ventilation, suggesting benefits in accelerating the weaning process and reducing mechanical ventilation duration.