Vaccine protection against the SARS-CoV-2 Omicron variant in macaques.

The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers and undetectable Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Moreover, virologic control correlated with both antibody and T cell responses. These data suggest that both humoral and cellular immune responses contribute to vaccine protection against a highly mutated SARS-CoV-2 variant.

Low-dose Ad26.COV2.S protection against SARS-CoV-2 challenge in rhesus macaques.

We previously reported that a single immunization with an adenovirus serotype 26 (Ad26)-vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge. To evaluate reduced doses of Ad26.COV2.S, 30 rhesus macaques were immunized once with 1 × 1011, 5 × 1010, 1.125 × 1010, or 2 × 109 viral particles (vp) Ad26.COV2.S or sham and were challenged with SARS-CoV-2. Vaccine doses as low as 2 × 109 vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125 × 1010 vp were required for protection in nasal swabs. Activated memory B cells and binding or neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show enhancement of disease. These data demonstrate that a single immunization with relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques, although a higher vaccine dose may be required for protection in the upper respiratory tract.

Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine.

The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12 µg lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n = 6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates.

Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques.

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic1-8. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques (Macaca mulatta) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes9,10. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.

Improving comparative analyses of Hi-C data via contrastive self-supervised learning.

Hi-C is a widely applied chromosome conformation capture (3C)-based technique, which has produced a large number of genomic contact maps with high sequencing depths for a wide range of cell types, enabling comprehensive analyses of the relationships between biological functionalities (e.g. gene regulation and expression) and the three-dimensional genome structure. Comparative analyses play significant roles in Hi-C data studies, which are designed to make comparisons between Hi-C contact maps, thus evaluating the consistency of replicate Hi-C experiments (i.e. reproducibility measurement) and detecting statistically differential interacting regions with biological significance (i.e. differential chromatin interaction detection). However, due to the complex and hierarchical nature of Hi-C contact maps, it remains challenging to conduct systematic and reliable comparative analyses of Hi-C data. Here, we proposed sslHiC, a contrastive self-supervised representation learning framework, for precisely modeling the multi-level features of chromosome conformation and automatically producing informative feature embeddings for genomic loci and their interactions to facilitate comparative analyses of Hi-C contact maps. Comprehensive computational experiments on both simulated and real datasets demonstrated that our method consistently outperformed the state-of-the-art baseline methods in providing reliable measurements of reproducibility and detecting differential interactions with biological meanings.

Recent advances in tunable solid-state emission based on α-cyanodiarylethenes: from molecular packing regulation to functional development.

The design and development of organic solid-state luminescent materials stand as crucial pillars within the realm of contemporary photofunctional materials. Overcoming challenges such as concentration quenching and achieving tailored luminescent properties necessitates a judicious approach to molecular structure design and the strategic utilization of diverse stimuli to modulate molecular packing patterns. Among the myriad candidates, α-cyanodiarylethenes (CAEs) emerge with distinctive solid-state luminescent attributes, capable of forming self-assembled packing structures with varying degrees of π-π stacking. This characteristic endows them with potential in the field of intelligent molecular responsive materials and optoelectronic devices. This tutorial review embarks on an exploration of design strategies geared towards attaining tunable solid-state emission through customized packing of CAEs. It explores the utilization of stimuli responses, including such as mechanical forces, light irradiation, solvent interactions, thermal influences, as well as the utilization of co-assembly methodologies. The overarching aim of this review is to provide a widely applicable platform fostering the flourishing development of modern organic photofunctional materials through integrating principles of molecular engineering, organic optoelectronics, and materials science.

Convenient Size Analysis of Nanoplastics on a Microelectrode.

Chemical recycling is a promising approach to reduce plastic pollution. Timely and accurate size analysis of produced nanoplastics is necessary to monitor the process and assess the quality of chemical recycling. In this work, a sandwich-type microelectrode sensor was developed for the size assessment of nanoplastics. ß-Mercaptoethylamine was modified on the microelectrode to enhance its surface positive charge density. Polystyrene (PS) nanoplastics were captured on the sensor through electrostatic interactions. Ferrocene was used as an electrochemical beacon and attached to PS via hydrophobic interactions. The results show a nonlinear dependence of the sensor's current response on the PS particle size. The size resolving ability of the microelectrode is mainly attributed to the small size of the electrode and the resulting attenuation of the electric field strength. For mixed samples with different particle sizes, this method can provide accurate average particle sizes. Through an effective pretreatment process, the method can be applied to PS nanoplastics with different surface properties, ensuring its application in evaluating different chemical recycling methods.

Geometric and Electronic Structure Modulation to Optimize the Charge Transfer of TiO2 for Ultrasensitive and Stable SERS Sensing.

Exploring the relationship between semiconductor structure and surface-enhanced Raman scattering (SERS) activity was essential for the development of ultrasensitive SERS substrates. Herein, we report an ytterbium atomic doping strategy to render TiO2 (Yb-TiO2) highly SERS sensitive superior to pure TiO2, with a detection limit as low as 1 × 10-9 M for 4-mercaptobenzoic acid. First-principles density functional theory calculations reveal that ytterbium doping leads to high electrostatic properties, allowing for significant charge transfer from molecules to semiconductors. Theoretical and experimental results indicate that Yb-TiO2 has a smaller band gap and higher density of states, which effectively enhance charge transfer between molecules and substrates, resulting in significant SERS activity. More importantly, Yb-TiO2 was particularly stable in air and acid solution and can be used for trace molecule detection in extreme environments. We demonstrate a promising approach to construct ultrasensitive SERS by optimizing the electronic structure induced by geometric structures.

Association of remnant cholesterol with decreased kidney function or albuminuria: a population-based study in the U.S.

BACKGROUND: Dyslipidemia is frequently exhibited in individuals with chronic kidney disease (CKD). Remnant cholesterol (RC), an emerging novel lipid marker, plays an elusive role in CKD progression. This study sought to investigate the association of RC with decreased kidney function or albuminuria in the general population of U.S. METHOD: Data were retrieved from the continuous 2001 to 2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Individuals aged between 18 and 70 years were included. RC was divided into quartiles. Albuminuria was defined by albumin-to-creatinine ratio (ACR) ≥30 mg/g, while reduced kidney function was described as an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2. Using a multivariable regression model, the association of RC with decreased eGFR or albuminuria was examined. The dose‒response relationship between RC and eGFR or ACR was also investigated using a restricted cubic spline (RCS) model. RESULTS: A total of 1551 (10.98%) participants with impaired renal function or albuminuria were identified. After multivariate adjustment, RC was not significantly associated with kidney function decline or albuminuria (odds ratio (OR) 1.24, 95% confidence interval (95% CI): 0.95, 1.61). However, a significantly inverse correlation was observed between RC and eGFR in a dose‒response manner (ß -2.12, 95% CI: -3.04, -1.21). This association remained consistent when stratifying data by gender, age, race, hypertension, diabetes and body mass index (BMI). CONCLUSION: A higher RC was significantly correlated with a lower eGFR in the general population. The role of RC in predicting kidney outcomes needed further investigation in prospective studies.

Osteoporosis screening using QCT-based cutoff value of Hounsfield units in patients with degenerative lumbar diseases.

PURPOSE: In patients with degenerative lumbar diseases, we aimed to establish the cutoff value of Hounsfield units (HU) for osteoporosis screening on the basis of the relationship between computed tomography (CT) HU value and volume bone mineral density (BMD) measured by quantitative computed tomography (QCT). METHODS: A total of 136 patients aged ≥ 50 years with degenerative lumbar diseases were retrospectively included. Their QCT-BMD of L1-2 were recorded, and the CT values of L1-2 were measured with the same CT images of QCT. The degree of bone loss was evaluated with the criteria based on QCT-BMD: cutoff value of 80 mg/cm3 for osteoporosis and cutoff value of 120 mg/cm3 for osteopenia. The cutoff of CT value was acquired according to the linear regression equation between CT value and QCT-BMD. RESULTS: The rate of osteoporosis, osteopenia, normal BMD was 33.8% (46/136), 51.5% (70/136), and 14.7% (20/136), respectively. The Pearson correlation coefficients between CT value and QCT-BMD were over 0.9 (P < 0.05). The cutoff of average CT value of L1-2 was calculated and adjusted to 110HU for osteoporosis and 160HU for osteopenia according the equation: average QCT-BMD of L1-2 = 0.76 âœ• average CT value of L1-2-0.46 (R2 = 0.931, P < 0.001). Cutoff value of 110HU was 91.2% (42/46) sensitive and 88.9% (80/90) specific for identifying osteoporosis. The cutoff value of 160HU was 95.0% (19/20) sensitive and 96.6% (112/116) specific for distinguishing normal BMD from abnormal BMD (osteoporosis and osteopenia). CONCLUSION: The CT value is effective in osteoporosis screening, and the QCT-based cutoff value is 110 HU for osteoporosis and 160 HU for osteopenia in the patients with degenerative lumbar disease.

MiR-143-5p regulates the proangiogenic potential of human dental pulp stem cells by targeting HIF-1α/RORA under hypoxia: A laboratory investigation in pulp regeneration.

AIM: Angiogenesis is a key event in the successful healing of pulp injuries, and hypoxia is the main stimulator of pulpal angiogenesis. In this study, we investigated the effect of hypoxia on the proangiogenic potential of human dental pulp stem cells (hDPSCs) and the role of miR-143-5p in the process. METHODOLOGY: Human dental pulp stem cells were isolated, cultured and characterized in vitro. Cobalt chloride (CoCl2) was used to induce hypoxia in hDPSCs. CCK-8 and Transwell assays were used to determine the effect of hypoxia on hDPSCs proliferation and migration. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting (WB) and ELISA were performed to assess the mRNA and protein levels of HIF-1α and angiogenic cytokines in hDPSCs. The effect of hypoxia on hDPSCs proangiogenic potential was measured in vitro using Matrigel tube formation and chick chorioallantoic membrane (CAM) assays. Recombinant lentiviral vectors were constructed to stably overexpress or inhibit miR-143-5p in hDPSCs, and the proangiogenic effects were assessed using qRT-PCR, WB, and tube formation assays. miR-143-5p target genes were identified and verified using bioinformatics prediction tools, dual-luciferase reporter assays and RNA pull-down experiments. Finally, a subcutaneous transplantation model in nude mice was used to determine the effects of hypoxia treatment and miR-143-5p overexpression/inhibition in hDPSCs in dental pulp regeneration. RESULTS: Hypoxia promotes hDPSCs proliferation, migration and proangiogenic potential. The in vivo experiments showed that hypoxia treatment (50 and 100 µM CoCl2) promoted pulp angiogenesis and dentine formation. In contrast to the levels of proangiogenic factors, miR-143-5p levels decreased with increasing CoCl2 concentration. miR-143-5p inhibition significantly promoted proangiogenic potential of hDPSCs, whereas miR-143-5p overexpression inhibited angiogenesis in vitro. Dual-luciferase reporter assay identified retinoic acid receptor-related orphan receptor alpha (RORA) as an miR-143-5p target gene in hDPSCs. RNA pull-down experiments demonstrated that HIF-1α and RORA were pulled down by biotin-labelled miR-143-5p, and the levels of HIF-1α and RORA bound to miR-143-5p in the hypoxia group were lower than those in the normoxia group. Inhibition of miR-143-5p expression in hDPSCs promoted ectopic dental pulp tissue regeneration. CONCLUSIONS: CoCl2-induced hypoxia promotes hDPSCs-driven paracrine angiogenesis and pulp regeneration. The inhibition of miR-143-5p upregulates the proangiogenic potential of hDPSCs under hypoxic conditions by directly targeting HIF-1α and RORA.

Chlorogenic acid improves the development of porcine parthenogenetic embryos by regulating oxidative stress and ameliorating mitochondrial function.

Chlorogenic acid (CGA) is an effective phenolic antioxidant that can scavenge hydroxyl radicals and superoxide anions. Herein, the protective effects and mechanisms leading to CGA-induced porcine parthenogenetic activation (PA) in early-stage embryos were investigated. Our results showed that 50 µM CGA treatment during the in vitro culture (IVC) period significantly increased the cleavage and blastocyst formation rates and improved the blastocyst quality of porcine early-stage embryos derived from PAs. Then, genes related to zygotic genome activation (ZGA) were identified and investigated, revealing that CGA can promote ZGA in porcine PA early-stage embryos. Further analysis revealed that CGA treatment during the IVC period decreased the abundance of reactive oxygen species (ROS), increased the abundance of glutathione and enhanced the activity of catalase and superoxide dismutase in porcine PA early-stage embryos. Mitochondrial function analysis revealed that CGA increased mitochondrial membrane potential and ATP levels and upregulated the mitochondrial homeostasis-related gene NRF-1 in porcine PA early-stage embryos. In summary, our results suggest that CGA treatment during the IVC period helps porcine PA early-stage embryos by regulating oxidative stress and improving mitochondrial function.

The relationship between circulating tumor cells in peripheral blood and clinical characteristics of pediatric neuroblastoma and prognostic evaluation.

This study investigates the correlation between circulating tumor cells (CTCs) in peripheral blood and the clinical characteristics and prognosis of advanced pediatric neuroblastoma (NB). We conducted a retrospective analysis of 144 children with advanced NB who underwent comprehensive treatment. Detailed clinical data were collected, and CTCs were detected using a negative enrichment method combined with immunofluorescence technology. Prognostic evaluation criteria and cutoff values for CTCs were established using ROC curve analysis. Univariate and Cox multivariate regression analyses identified independent risk factors impacting prognosis. Patients were categorized into high and low-expression groups based on optimal cutoff values determined with X-tile software. The high expression group had a significantly higher incidence of disease progression (p < 0.001), maximum tumor diameter ≥10 cm (p = 0.004), undifferentiated subtype (p = 0.034), and stage IV disease (p = 0.007) compared to the low expression group. CTCs were notably higher in patients with progression compared to those with mitigation (p < 0.001), in those with maximum tumor diameter ≥10 cm compared to <10 cm (p < 0.001), and in stage IV compared to stage III patients (p = 0.036). The AUC values for maximum tumor diameter, degree of differentiation, and tumor stage were 0.703, 0.669, 0.574, and 0.598, respectively. The detection of CTCs provides significant insights into the clinical characteristics and prognosis of advanced pediatric NB, highlighting its potential as a prognostic tool.

Depriving Tumor Cells of Ways to Metastasize: Ferroptosis Nanotherapy Blocks Both Hematogenous Metastasis and Lymphatic Metastasis.

Blood and lymph are two main pathways of tumor metastasis; however, hematogenous metastasis and lymphatic metastasis are difficult to inhibit simultaneously. Ferroptosis provides a new breakthrough for metastasis inhibition, but how to effectively trigger ferroptosis in tumor cells remains a major challenge. Metastatic tumor cells are prone to ferroptosis in blood, while they may be protected from ferroptosis in lymph. In this study, a nanoplatform DA/RSL3 was constructed for the intracellular codelivery of the polyunsaturated arachidonic acid (AA) and the GPX4 inhibitor RSL3, which could not only induce ferroptosis but also alleviate ferroptosis resistance. As a result, DA/RSL3 effectively triggered ferroptosis in tumor cells, thereby impairing the ability of tumor cells to metastasize in both blood and lymph. Furthermore, a fucoidan blocking strategy was proposed to maximize the efficacy of DA/RSL3. Fu+DA/RSL3 showed excellent efficacy in 4T1 tumor-bearing mice. This ferroptosis nanotherapy is promising for metastatic cancer treatment.

Effect of two different modalities of hysterectomy on wound infection and wound dehiscence in obese patients.

This research intended to investigate the influence of the operation of both kinds of hysterectomies in the risk of wound infection and the degree of wound dehiscence. Both of them were open field and laparoscope. In this research, we looked into four databases: PubMed, Web of Science, Embase and Cochrane Library. Research was conducted on various operative methods for hysterectomy in obese patients between 2000 and October 2023. Two independent investigators performed an independent review of the data, established the inclusion and exclusion criteria, and managed the results with Endnote software. It also evaluated the quality of the included literature. Finally, the data were analysed with RevMan 5.3. This study involved 874 cases, 387 cases received laparoscopy and 487 cases received open access operation. Our findings indicate that there is a significant reduction in the rate of post-operative wound infection among those who have received laparoscopy compared with who have received open surgical procedures (odds ratio [OR], 0.04; 95% confidence interval [CI], 0.01-0.15; p < 0.001); There was no statistical difference between the rate of post-operative wound dehiscence and those who received laparotomy compared with those who received open surgical procedures (OR, 0.33; 95% CI, 0.10-1.11; p = 0.07); The estimated amount of blood lost during the operation was less in the laparoscopy group compared with the open procedure (mean difference, -123.72; 95% CI, -215.16 to -32.28; p = 0.008). Generally speaking, the application of laparoscopy to overweight women who have had a hysterectomy results in a reduction in the expected amount of bleeding during surgery and a reduction in the risk of post-operative wound infections.

The Linkage-Moderated Covalent Organic Frameworks with C=N and NN on Charge Transfer Kinetics Towards the Robust Photocatalytic Hydrogen Activity.

Since the linkages structured in covalent organic frameworks (COFs) usually impact the charge transfer behavior during photocatalytic hydrogen evolution reaction (pc-HER), linkage dependence on charge transfer kinetics should be further claimed. Herein, COFs with N-based linkages and pyrene-based building nodes are constructed to enable us to obtain new clues about the charge transfer behavior and evolution tendency relevant to linkages at a molecular level for pc-HER. It is demonstrated that photo-excited electrons preferably move to the N sites in C=N linkage for pc-HER and are trapped around NN linkage as well. A high electron transfer rate does not point to high photocatalytic activity directly, while a small difference between the electron transfer rate and electron recombination rate ΔkCT - CR predicts the inefficiency of charge transfer in Azod-COFs. Contrarily, large value of ΔkCT - CR in the case of Benzd-COFs, demonstrats an unimpeded charge transfer process to result in boosted pc-HER rate (2027.3 µmol h-1 g-1 ). This work offers a prominent strategy for the reasonable design of efficient photocatalysts at the molecular level for structural regulation and achieves an efficient charge transfer process for the pc-HER process.

Rapid Loss of CD4 T Cells by Pyroptosis during Acute SIV Infection in Rhesus Macaques.

The mechanisms underlying depletion of CD4 T cells during acute HIV-1 infection are not well understood. Here we show that caspase-1-induced pyroptosis, a highly inflammatory programmed cell death pathway, is the dominant mechanism responsible for the rapid depletion of CD4 T cells in gut-associated lymphatic tissue (GALT), spleen, and lymph nodes during acute simian immunodeficiency virus (SIV) infection in rhesus macaques. Upregulation of interferon-gamma inducible factor 16, a host DNA sensor that triggers pyroptosis, was also observed in tissue-resident CD4 T cells and correlated with viral loads and CD4 T cell loss. In contrast, caspase-3-mediated apoptosis and viral cytotoxicity only accounted for a small fraction of CD4 T cell death. Other programmed cell death mechanisms, including mitochondria-induced caspase-independent cell death, necroptosis, and autophagy, did not significantly contribute to CD4 T cell depletion. These data support a model in which caspase-1-mediated pyroptosis is the principal mechanism that results in CD4 T cell loss in the GALT and lymphoid organs and release of proinflammatory cytokines. These findings contribute to our understanding of the pathogenesis of acute SIV infection and have important implications for the development of therapeutic strategies. IMPORTANCE Different mechanisms for CD4 T cell depletion during acute HIV-1 infection have been proposed. In this study, we demonstrate that in early simian immunodeficiency virus infection, depletion of CD4 T cells is primarily due to pyroptosis. Other mechanisms may also contribute in a minor way to CD4 T cell depletion.

Loss of microglial EED impairs synapse density, learning, and memory.

The embryonic ectoderm development (EED) is a core component of the polycomb-repressive complex 2 (PRC2) whose mutations are linked to neurodevelopmental abnormalities, intellectual disability, and neurodegeneration. Although EED has been extensively studied in neural stem cells and oligodendrocytes, its role in microglia is incompletely understood. Here, we show that microglial EED is essential for synaptic pruning during the postnatal stage of brain development. The absence of microglial EED at early postnatal stages resulted in reduced spines and impaired synapse density in the hippocampus at adulthood, accompanied by upregulated expression of phagocytosis-related genes in microglia. As a result, deletion of microglial Eed impaired hippocampus-dependent learning and memory in mice. These results suggest that microglial EED is critical for normal synaptic and cognitive functions during postnatal development.

The impact of the national volume-based procurement policy on the use of policy-related drugs in Nanjing: an interrupted time-series analysis.

BACKGROUND: In September 2019, the "4 + 7" centralized procurement pilot program was expanded nationwide aiming at reducing drug prices by means of volume-based procurement and using accredited generic drugs for branded drug substitutes. Given the current uncertain effect of the policy outside pilot areas, this study was conducted to evaluate the impact of the National Volume-based Procurement policy on the use of policy-related drugs after expansion. METHOD: A single-group interrupted time series was applied using drug purchase data, covering 25 months from December 2018 to December 2020. Drugs related to the centralized procurement policy were selected as samples, including 25 first-batch policy-related drugs and 56 alternative drugs. Centralized procured drugs can be divided into bid-winning and non-winning products, where non-winning products were sorted into generic and branded drugs, and alternative products were classified according to different degrees of substitution. Purchase volume, expenditures, and daily costs were measured. RESULTS: After the implementation of the policy, a significant increase was associated with the volume of bid-winning drugs (p < 0.001) and the volume of generic and branded drugs decreased immediately. The DDDc of drugs under the same generic name significantly reduced (an instantaneous drop of bid-winning drugs by approximately 25%, 7.62 CNY for generics and 3.07 CNY for branded drugs), saving 48.2 million CNY of drug expenditures. The policy has a significant effect on the drug for the treatment of cardiovascular diseases and exerted little influence on the drug for the treatment of nervous diseases, and the substitution of generics for antitumor-branded drugs was not obvious. In addition, the procurement volume of alternative drugs appeared to be a "carry-over". CONCLUSIONS: These findings indicated that the policy demonstrated positive effects in terms of price reductions and cost savings and accelerated the substitution of generics against branded drugs. The "patent cliff" for branded drugs has gradually emerged. Besides, a short-term "spillover effect" of the volume of alternative drugs was observed, requiring special attention and vigilance.

Cost-effectiveness of preimplantation genetic testing for aneuploidy for women with subfertility in China: an economic evaluation using evidence from the CESE-PGS trial.

BACKGROUND: There are a large number of infertile couples in China, but its treatment is notoriously expensive and not currently covered by insurance. The utility of preimplantation genetic testing for aneuploidy as an adjunct to in vitro fertilization has been debated. OBJECTIVE: To investigate the cost-effectiveness of preimplantation genetic testing for aneuploidy (PGT-A) versus conventional technology in in vitro fertilization (IVF) from the perspective of the healthcare system in China. METHODS: Following the exact steps in the IVF protocol, a decision tree model was developed, based on the data from the CESE-PGS trial and using cost scenarios for IVF in China. The scenarios were compared for costs per patient and cost-effectiveness. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to confirm the robustness of the findings. MAIN OUTCOME MEASURES: Costs per live birth, Costs per patient, Incremental cost-effectiveness for miscarriage prevention. RESULTS: The average costs per live birth of PGT-A were estimated as ¥39230.71, which is about 16.8% higher than that of the conventional treatment. Threshold analysis revealed that PGT-A would need to increase the pregnancy rate of 26.24-98.24% or a cost reduction of ¥4649.29 to ¥1350.71 to achieve the same cost-effectiveness. The incremental costs per prevented miscarriage was approximately ¥45600.23. The incremental cost-effectiveness for miscarriage prevention showed that the willingness to pay would be ¥43422.60 for PGT-A to be cost-effective. CONCLUSION: The present cost-effectiveness analysis demonstrates that embryo selection with PGT­A is not suitable for routine applications from the perspective of healthcare providers in China, given the cumulative live birth rate and the high costs of PGT­A.