Photoswitched Stereodivergent Synthesis of Allylic Sulfones.

The present Letter demonstrates a photoswitched stereodivergent synthesis of allylic sulfones from sodium sulfinates, triphenylvinylphosphonium chloride, and (hetero)aromatic aldehydes in a single step. Mechanistically, cis-allylic sulfones, generated from the unstabilized ylide intermediates and aldehydes in situ, could be finally converted to trans-allylic sulfones via photochemical isomerization in the presence of a catalytic amount of bis(2-thienyl) ketone.

Residual Immunity from Smallpox Vaccination and Possible Protection from Mpox, China.

Among persons born in China before 1980 and tested for vaccinia virus Tiantan strain (VVT), 28.7% (137/478) had neutralizing antibodies, 71.4% (25/35) had memory B-cell responses, and 65.7% (23/35) had memory T-cell responses to VVT. Because of cross-immunity between the viruses, these findings can help guide mpox vaccination strategies in China.

Durability and cross-reactive immune memory to SARS-CoV-2 in individuals 2 years after recovery from COVID-19: a longitudinal cohort study.

BACKGROUND: SARS-CoV-2-specific adaptive immunity more than 1 year after initial infection has not been well characterised. The aim of this study was to investigate the durability and cross-reactivity of immunological memory acquired from natural infection against SARS-CoV-2 in individuals recovered from COVID-19 2 years after infection. METHODS: In this longitudinal cohort study, we recruited patients who had recovered from laboratory-confirmed COVID-19 and were discharged from Jinyintan Hospital (Wuhan, China) between Jan 7 and May 29, 2020. We carried out three successive follow-ups between June 16 and Sept 3, 2020 (6 months), Dec 16, 2020, and Feb 7, 2021 (1 year), and Nov 16, 2021, and Jan 10, 2022 (2 years), in which blood samples were taken. We included participants who did not have re-infection or receive a SARS-CoV-2 vaccination (infected-unvaccinated), and participants who received one to three doses of inactivated vaccine 1-2 years after infection (infected-vaccinated). We evaluated the presence of IgG antibodies, neutralising antibodies, and memory B-cell and memory T-cell responses against the prototype strain and delta and omicron variants. FINDINGS: In infected-unvaccinated participants, neutralising antibody titres continually declined from 6-month to 2-year follow-up visits, with a half-life of about 141·2 days. Neutralising antibody responses to omicron sublineages (BA.1, BA.1.1, BA.2, BA.4/5, BF.7, BQ.1, and XBB) were poor. Memory B-cell responses to the prototype strain were retained at 2 years and presented cross-reactivity to the delta and omicron BA.1 variants. The magnitude of interferon γ and T-cell responses to SARS-CoV-2 were not significantly different between 1 year and 2 years after infection. Multifunctional T-cell responses against SARS-CoV-2 spike protein and nucleoprotein were detected in most participants. Recognition of the BA.1 variant by memory T cells was not affected in most individuals. The antibody titres and the frequencies of memory B cells, but not memory T cells, increased in infected-vaccinated participants after they received the inactivated vaccine. INTERPRETATION: This study improves the understanding of the duration of SARS-CoV-2-specific immunity without boosting, which has implications for the design of vaccination regimens and programmes. Our data suggest that memory T-cell responses primed by initial viral infection remain highly cross-reactive after 2 years. With the increasing emergence of variants, effective vaccines should be introduced to boost neutralising antibody and overall T-cell responses to newly emerged SARS-CoV-2 variants. FUNDING: Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Fundamental Research Funds for the Central Universities for Peking Union Medical College, Beijing Natural Science Foundation, UK Medical Research Council.

Chiral Gd-DOTA as a Versatile Platform for Hepatobiliary and Tumor Targeting MRI Contrast Agents.

The leakage of gadolinium ions (Gd3+) from commercial Gd3+-based contrast agents (GBCAs) in patients is currently the major safety concern in clinical magnetic resonance imaging (MRI) scans, and the lack of task-specific GBCAs limits its usage in the early detection of disease and imaging of specific biological regions. Herein, ultrastable GBCAs were constructed via decorating chiral Gd-DOTA with a phenylic analogue to one of the pendent arms, and the stability constant was determined as high as 27.08, accompanied by negligible decomplexation in 1 M of HCl over 2 years. A hepatic-specific chiral Gd-DOTA was screened out as a potential alternative to commercial Gd-EOB-DTPA, while combination with functional molecules favored chiral Gd-DOTA as tumor targeting probes. Therefore, the novel chiral Gd-DOTA is believed to be an ideal platform for designing the next generation of GBCAs for various clinical purposes due to its outstanding inert nature.

Machine learning prediction model for the rupture status of middle cerebral artery aneurysm in patients with hypertension: a Chinese multicenter study.

Background: Hypertension is a common comorbidity in patients with unruptured intracranial aneurysms and is closely associated with the rupture of aneurysms. However, only a few studies have focused on the rupture risk of aneurysms comorbid with hypertension. This retrospective study aimed to construct prediction models for the rupture of middle cerebral artery (MCA) aneurysm associated with hypertension using machine learning (ML) algorithms, and the constructed models were externally validated with multicenter datasets. Methods: We included 322 MCA aneurysm patients comorbid with hypertension who were being treated in four hospitals. All participants underwent computed tomography angiography (CTA), and aneurysm morphological features were measured. Clinical characteristics included sex, age, smoking, and hypertension history. Based on the clinical and morphological characteristics, the training datasets (n=277) were used to fit the ML algorithms to construct prediction models, which were externally validated with the testing datasets (n=45). The prediction performances of the models were assessed by receiver operating characteristic (ROC) curves. Results: The areas under the ROC curve (AUCs) of the k-nearest-neighbor (KNN), neural network (NNet), support vector machine (SVM) and logistic regression (LR) models in the training datasets were 0.83 [95% confidence interval (CI): 0.78-0.88], 0.87 (95% CI: 0.82-0.92), 0.91 (95% CI: 0.88-0.95), and 0.83 (95% CI: 0.77-0.88), respectively, and in the testing datasets were 0.74 (95% CI: 0.59-0.89), 0.82 (95% CI: 0.69-0.94), 0.73 (95% CI: 0.58-0.88), and 0.76 (95% CI: 0.61-0.90), respectively. The aspect ratio (AR) was ranked as the most important variable in the ML models except for NNet. Further analysis showed that the AR had good diagnostic performance, with AUC values of 0.75 in the training datasets and 0.77 in the testing datasets. Conclusions: The ML models performed reasonably accurately in predicting MCA aneurysm rupture comorbid with hypertension. AR was demonstrated as the leading predictor for the rupture of MCA aneurysm with hypertension.

Omicron BA.1 breakthrough infections in inactivated COVID-19 vaccine recipients induced distinct pattern of antibody and T cell responses to different Omicron sublineages.

The adaptive immunity against SARS-CoV-2 prototype strain and Omicron sublineages induced by BA.1 breakthrough infection in vaccinees of inactivated COVID-19 vaccines have not been well characterized. Here, we report that BA.1 breakthrough infection induced mucosal sIgA and resulted in higher IgG titers against prototype strain and Omicron sublineages in vaccinees than in vaccine naïve-infected individuals. BA.1 breakthrough infection boosted antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis to prototype strain and BA.1, BA.1.1, BA.2, BA.2.12.1, and BA.2.75 but not BA.4/5 and induced neutralization against prototype strain and BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.75, and BA.4/5 but not BF.7, BQ.1, and XBB. In total, BA.1 breakthrough infection individuals produced less extensive sIgA, plasma IgG and NAb responses against Omicron sublineages compared with those against prototype strain. Further, BA.1 breakthrough infection induced recall B cell response to prototype strain and Omicron variant, primarily targeting memory B cells producing conserved epitopes. Memory T cell responses against Omicron is largely preserved. Individuals with vaccine booster did not induce more beneficial immune responses to Omicron sublineages upon BA.1 breakthrough infection than those with primary vaccine dose only. The breakthrough infection individuals produced stronger adaptive immunity than those of inactivated vaccine-healthy individuals. These data have important implications for understanding the vaccine effectiveness and adaptive immunity to breakthrough infection in individuals fully immunized with inactivated vaccines. Omicron sublineages, especially for those emerged after BA.4/5 strain, evade NAb responses induced by BA.1 breakthrough infection. It is urgent to optimize the vaccine immunogen design and formulations to SARS-CoV-2 variants.

Humoral responses after inactivated COVID-19 vaccination in individuals with and without prior SARS-CoV-2 infection: A prospective cohort study.

We evaluated and compared humoral immune responses after inactivated coronavirus disease 2019 (COVID-19) vaccination among naïve individuals, asymptomatically infected individuals, and recovered patients with varying severity. In this multicenter, prospective cohort study, blood samples from 666 participants were collected before and after 2 doses of inactivated COVID-19 vaccination. Among 392 severe acute respiratory syndrome coronavirus 2-naïve individuals, the seroconversion rate increased significantly from 51.8% (median antispike protein pan-immunoglobulins [S-Igs] titer: 0.8 U/ml) after the first dose to 96% (median S-Igs titer: 79.5 U/ml) after the second dose. Thirty-two percent of naïve individuals had detectable neutralizing antibodies (NAbs) against the original strain but all of them lost neutralizing activity against the Omicron variant. In 274 individuals with natural infection, humoral immunity was significantly improved after a single vaccine dose, with median S-Igs titers of 596.7, 1176, 1086.5, and 1828 U/ml for asymptomatic infections, mild cases, moderate cases, and severe/critical cases, respectively. NAb titers also improved significantly. However, the second dose did not substantially increase antibody levels. Although a booster dose is needed for those without infection, our findings indicate that recovered patients should receive only a single dose of the vaccine, regardless of the clinical severity, until there is sufficient evidence to confirm the benefits of a second dose.

The modified computed tomography severity index combined with low skeletal muscle mass can better predict the severity of hypertriglyceridemia-induced pancreatitis.

BACKGROUND: Body composition parameters are associated with hypertriglyceridemia-induced pancreatitis (HTGP). This study investigated the association between the quantity of muscle assessed using computed tomography (CT) and the severity of HTGP. METHODS: The modified CT severity index (MCTSI) was calculated from admission examination data. Patients' characteristics and body composition parameters were collected. Univariate and multivariate logistic regression analyses were also performed. The receiver operating characteristic curves and corresponding area under the curves (AUC) were calculated to test the efficiency of the model. A nomogram was then constructed. RESULTS: Of the 175 included patients, 138 were male, of which 85 had moderately severe to severe HTGP. Patients with low skeletal muscle mass (LSMM) and high MCTSI were significantly more likely to have moderately severe to severe HTGP. Patients with LSMM had lower body mass index, lower HDL-C level, higher amylase level, prevalence of surgery, shorter umbilical waist circumference, and longer length of hospital stay. Univariate and multivariate logistic regression analyses confirmed that female sex, lipase, total cholesterol, LSMM-MCTSI (P = .004, odds ratio = 23.105), and albumin were risk factors. The TOTAL model that combined LSMM-MCTSI and clinical risk parameters performed best (AUCs = 0.875), followed by other models (LSMM-MCTSI: AUCs = 0.762, MCTSI: AUCs = 0.728). The Delong test revealed significant difference. Finally, a nomogram was developed to predict the severity of HTGP. CONCLUSION: The performance of MCTSI in predicting severity can be improved by considering LSMM, which is a promising strategy for the treatment of HTGP.

SARS-CoV-2-specific antibody and T-cell responses 1 year after infection in people recovered from COVID-19: a longitudinal cohort study.

Background: The memory immune response is crucial for preventing reinfection or reducing disease severity. However, the robustness and functionality of the humoral and T-cell response to SARS-CoV-2 remains unknown 12 months after initial infection. The aim of this study is to investigate the durability and functionality of the humoral and T-cell response to the original SARS-CoV-2 strain and variants in recovered patients 12 months after infection. Methods: In this longitudinal cohort study, we recruited participants who had recovered from COVID-19 and who were discharged from the Wuhan Research Center for Communicable Disease Diagnosis and Treatment at the Chinese Academy of Medical Sciences, Wuhan, China, between Jan 7 and May 29, 2020. Patients received a follow-up visit between Dec 16, 2020, and Jan 27, 2021. We evaluated the presence of IgM, IgA, and IgG antibodies against the SARS-CoV-2 nucleoprotein, Spike protein, and the receptor-binding domain 12 months after initial infection, using ELISA. Neutralising antibodies against the original SARS-CoV-2 strain, and the D614G, beta (B.1.351), and delta (B.1.617.2) variants were analysed using a microneutralisation assay in a subset of plasma samples. We analysed the magnitude and breadth of the SARS-CoV-2-specific memory T-cell responses using the interferon γ (IFNγ) enzyme-linked immune absorbent spot (ELISpot) assay and intracellular cytokine staining (ICS) assay. The antibody response and T-cell response (ie, IFN-γ, interleukin-2 [IL-2], and tumour necrosis factor α [TNFα]) were analysed by age and disease severity. Antibody titres were also analysed according to sequelae symptoms. Findings: We enrolled 1096 patients, including 289 (26·4%) patients with moderate initial disease, 734 (67·0%) with severe initial disease, and 73 (6·7%) with critical initial disease. Paired plasma samples were collected from 141 patients during the follow-up visits for the microneutralisation assay. PBMCs were collected from 92 of 141 individuals at the 12-month follow-up visit, of which 80 were analysed by ELISpot and 92 by ICS assay to detect the SARS-CoV-2-specific memory T-cell responses. N-IgG (899 [82·0%]), S-IgG (1043 [95·2%]), RBD-IgG (1032 [94·2%]), and neutralising (115 [81·6%] of 141) antibodies were detectable 12 months after initial infection in most individuals. Neutralising antibodies remained stable 6 and 12 months after initial infection in most individuals younger than 60 years. Multifunctional T-cell responses were detected for all SARS-CoV-2 viral proteins tested. There was no difference in the magnitude of T-cell responses or cytokine profiles in individuals with different symptom severity. Moreover, we evaluated both antibody and T-cell responses to the D614G, beta, and delta viral strains. The degree of reduced in-vitro neutralising antibody responses to the D614G and delta variants, but not to the beta variant, was associated with the neutralising antibody titres after SARS-CoV-2 infection. We also found poor neutralising antibody responses to the beta variant; 83 (72·2%) of 115 patients showed no response at all. Moreover, the neutralising antibody titre reduction of the recovered patient plasma against the delta variant was similar to that of the D614G variant and lower than that of the beta variant. By contrast, T-cell responses were cross-reactive to the beta variant in most individuals. Importantly, T-cell responses could be detected in all individuals who had lost the neutralising antibody response to SARS-CoV-2 12 months after the initial infection. Interpretation: SARS-CoV-2-specific neutralising antibody and T-cell responses were retained 12 months after initial infection. Neutralising antibodies to the D614G, beta, and delta viral strains were reduced compared with those for the original strain, and were diminished in general. Memory T-cell responses to the original strain were not disrupted by new variants. This study suggests that cross-reactive SARS-CoV-2-specific T-cell responses could be particularly important in the protection against severe disease caused by variants of concern whereas neutralising antibody responses seem to reduce over time. Funding: Chinese Academy of Medical Sciences, National Natural Science Foundation, and UK Medical Research Council.