Immunotherapy Guided by Immunohistochemistry PD-L1 Testing for Patients with NSCLC: A Microsimulation Model-Based Effectiveness and Cost-Effectiveness Analysis.

BACKGROUND: On the basis of immunohistochemistry PD-L1 testing results, patients with advanced non-small cell lung cancer (NSCLC) are treated differently. Theoretically, patients with high PD-L1 expression (50% or 1%) should receive PD-1 monotherapy for fewer adverse reactions and cost savings from avoiding chemotherapy; however, there is controversy surrounding the cut-off criteria (1% or 50%) for immunohistochemistry testing and threshold for PD-1 monotherapy. OBJECTIVE: This study aims to predict the effectiveness and cost-effectiveness of different immunotherapy strategies for patients with NSCLC in China from the healthcare system perspective. PATIENTS AND METHODS: A microsimulation model was developed to evaluate the effectiveness and cost-effectiveness of three treatment strategies: PD-L1 testing (1%) (PD-1 monotherapy for those with PD-L1 expression at 1% threshold, and combination with chemotherapy for others with immunohistochemistry testing), PD-L1 testing (50%) (PD-1 monotherapy for those with PD-L1 expression at 50% threshold, and combination with chemotherapy for others with immunohistochemistry testing), and No PD-L1 testing (PD-1 combined with chemotherapy without immunohistochemistry testing). The model assumed 1000 patients per strategy, with each patient entering a unique clinical path prior to receiving treatment on the basis of PD-L1 test results. Clinical inputs were derived from clinical trials. Cost and utility parameters were obtained from the database and literature. One-way probabilistic sensitivity analyses (PSA) and six scenario analyses were used to test the model's robustness. RESULTS: The study revealed a hierarchy of survival benefits across three strategies, with No PD-L1 testing demonstrating the most survival advantage, followed by PD-L1 testing (50%), and finally, PD-L1 testing (1%). The comparative analysis demonstrated that No PD-L1 testing significantly enhanced overall survival (OS) (HR 0.85, 95% CI 0.78-0.93), progression-free survival (HR 0.82, 95% CI 0.75-0.90), and progression-free2 survival (PFS2) (HR 0.91, 95% CI 0.83-0.99) when juxtaposed against PD-L1 testing (1%). However, these improvements were not as pronounced when compared with PD-L1 testing (50%), particularly in relation to PFS, PFS2, and OS. The cost-effectiveness analysis further unveiled incremental cost-utility ratios (ICUR), with No PD-L1 testing versus PD-L1 testing (50%) at $34,003 per quality-adjusted life year (QALY) and No PD-L1 testing versus PD-L1 testing (1%) at $34,804 per QALY. In parallel, the ICUR for PD-L1 testing (50%) versus PD-L1 testing (1%) stood at $35,713 per QALY. Remarkably, the PSA result under a willingness-to-pay (WTP) threshold of $10,144 per QALY, with a 100% probability, demonstrated PD-L1 testing (1%) as the most cost-effective option. CONCLUSIONS: The survival benefits of PD-1 monotherapy for high expression with PD-L1 immunohistochemistry testing are inferior to those of PD-1 combined with chemotherapy without testing, but it is found to be more cost-effective at the WTP thresholds in China and holds great potential in increasing affordability and reducing the economic burden.

Comparative Cost-Effectiveness Analysis of Respiratory Syncytial Virus Vaccines for Older Adults in Hong Kong.

Two respiratory syncytial virus (RSV) vaccines (AREXVY® and ABRYSVO®) were recently approved for older adults in the US. This study aimed to evaluate the cost-effectiveness of AREXVY® and ABRYSVO® from the Hong Kong public healthcare provider's perspective. A two-year decision-analytical model was developed to examine the outcomes of a single RSV vaccination (AREXVY® or ABRYSVO®) compared to no vaccination. Primary outcomes included RSV-related health outcomes, direct medical costs, quality-adjusted life-year (QALY) loss, and incremental cost per QALY (ICER). RSV vaccines are not yet marketed in Hong Kong, base-case analysis, therefore, benchmarked US RSV vaccine prices at 4 levels (25%, 50%, 75%, 100%). AREXVY® and ABRYSVO® (versus no vaccination) gained 0.000568 QALY and 0.000647 QALY, respectively. ICERs of ABRYSVO® (26,209 USD/QALY) and AREXVY® (47,485 USD/QALY) were lower than the willingness-to-pay threshold (49,594 USD/QALY) at 25% US vaccine price. The RSV attack rate was a common influential factor at all vaccine price levels. The probabilities of AREXVY® and ABRYSVO® to be most cost-effective were 0.10% and 97.68%, respectively, at 25% US vaccine price. Single vaccination of ABRYSVO® or AREXVY® for older adults appears to gain QALYs over 2 years in Hong Kong. The cost-effectiveness of AREXVY® and ABRYSVO® is subject to vaccine price and RSV attack rate.

Chemodivergence in Pd-catalyzed desymmetrization of allenes: enantioselective [4+3] cycloaddition, desymmetric allenylic substitution and enynylation.

A class of prochiral allenylic di-electrophiles have been introduced for the first time as three-atom synthons in cycloadditions, and a new type of [4+3] cycloaddition involving transition metal-catalyzed enantioselective sequential allenylic substitution has been successfully developed, enabling challenging seven-membered exocyclic axially chiral allenes to be accessed in good yields with good enantioselectivity. Through the addition of a catalytic amount of ortho-aminoanilines or ortho-aminophenols, the racemization of the [4+3] cycloaddition products is effectively suppressed. Mechanistic studies reveal that elusive Pd-catalyzed enantioselective intramolecular allenylic substitution rather than intermolecular allenylic substitution is the enantio-determining step in this cycloaddition. By tuning the ligands, a Pd-catalyzed enantioselective desymmetric allenylic substitution leading to linear axially chiral tri-substituted allenes or a Pd-catalyzed tandem desymmetric allenylic substitution/ß-vinylic hydrogen elimination (formal enynylation) leading to multi-functionalized 1,3-enynes is achieved chemodivergently.

Web-based intervention for improving influenza vaccination in pregnant women: a cost-effectiveness analysis.

A website with vaccine information and interactive social media was reported to improve maternal influenza vaccine uptake. This study aimed to evaluate cost-effectiveness of a web-based intervention on influenza vaccine uptake among pregnant women from the perspective of US healthcare providers. A one-year decision-analytic model estimated outcomes in a hypothetical cohort of pregnant women with: (1) website with vaccine information and interactive social media (intervention group), and (2) usual care (usual care group). Primary measures included influenza infection, influenza-related hospitalization, mortality, direct medical cost, and quality-adjusted life-year (QALY) loss. In base-case analysis, intervention group reduced cost (by USD28), infection (by 28 per 1,000 pregnant women), hospitalization (by 1.226 per 1,000 pregnant women), mortality (by 0.0036 per 1,000 pregnant women), and saved 0.000305 QALYs versus usual care group. Relative improvement of vaccine uptake by the intervention and number of pregnant women in the healthcare system were two influential factors identified in deterministic sensitivity analysis. The intervention was cost-effective in 99.5% of 10,000 Monte Carlo simulations (at willingness-to-pay threshold 50,000 USD/QALY). A website with vaccine information and interactive social media to promote influenza vaccination for pregnant women appears to reduce direct medical costs and gain QALYs from the perspective of US healthcare providers.

Standard diagnostics with and without urine-based lipoarabinomannan testing for tuberculosis disease in HIV-infected patients in a high-burden setting-A cost-effectiveness analysis.

BACKGROUND: Recent clinical findings reported the reduced mortality associated with treatment guided by sputum-based molecular test with urine-based lipoarabinomannan (LAM) assay for tuberculosis (TB) disease in HIV-infected individuals. We aimed to evaluate the cost-effectiveness of sputum-based Xpert tests with and without urine-based LAM assays among HIV-infected individuals with signs and symptoms of TB disease (TBD) from the perspective of South African healthcare providers. METHODS: A one-year decision-analytic model was constructed to simulate TB-related outcomes of 7 strategies: Sputum smear microscope (SSM), Xpert, Xpert Ultra, Xpert with AlereLAM, Xpert Ultra with AlereLAM, Xpert with FujiLAM, and Xpert Ultra with FujiLAM, in a hypothetical cohort of adult HIV-infected individuals with signs and symptoms of TB. The model outcomes were TB-related direct medical cost, mortality, early treatment, disability-adjusted life-years (DALYs) and incremental cost per DALY averted (ICER). The model inputs were retrieved from literature and public data. Base-case analysis and sensitivity analysis were conducted. RESULTS: In the base-case analysis, the Xpert Ultra with FujiLAM strategy showed the highest incidence of early treatment (267.7 per 1000 tested) and lowest mortality (29.0 per 1000 tested), with ICER = 676.9 USD/DALY averted. Probabilistic sensitivity analysis of 10,000 Monte Carlo simulations showed the cost-effective probability of Xpert Ultra with FujiLAM was the highest of all 7 strategies at the willingness-to-pay (WTP) threshold >202USD/DALY averted. CONCLUSION: Standard sputum-based TB diagnostic Xpert Ultra with urine-based FujiLAM for TBD testing in HIV-infected individuals appears to be the preferred cost-effective strategy from the perspective of the health service provider of South Africa.

Grass-Legume Mixture with Rhizobium Inoculation Enhanced the Restoration Effects of Organic Fertilizer.

The establishment of artificial grassland is crucial in restoring degraded grassland and resolving the forage-livestock conflict, and the application of organic fertilizer and complementary seeding of grass-legume mixture are effective methods to enhance grass growth in practice. However, its mechanism behind the underground is largely unclear. Here, by utilizing organic fertilizer in the alpine region of the Qinghai-Tibet Plateau, this study assessed the potential of grass-legume mixtures with and without the inoculation of Rhizobium for the restoration of degraded grassland. The results demonstrated that the application of organic fertilizer can increase the forage yield and soil nutrient contents of degraded grassland, and they were 0.59 times and 0.28 times higher than that of the control check (CK), respectively. The community composition and structure of soil bacteria and fungi were also changed by applying organic fertilizer. Based on this, the grass-legume mixture inoculated with Rhizobium can further increase the contribution of organic fertilizer to soil nutrients and thus enhance the restoration effects for degraded artificial grassland. Moreover, the application of organic fertilizer significantly increased the colonization of gramineous plant by native mycorrhizal fungi, which was ~1.5-2.0 times higher than CK. This study offers a basis for the application of organic fertilizer and grass-legume mixture in the ecological restoration of degraded grassland.

[Effects of the Transformation from Natural Alpine Grassland to Mixed Artificial Grassland on the Characteristics of Soil Microbial Community].

This study aimed to analyze the effects of the transformation from natural alpine grassland (NAG) to mixed artificial grassland (MAG) on the characteristics of soil microbial community. We used Illumina Miseq high-throughput sequencing technology to investigate the soil microbial community of natural grassland and mixed artificial grassland. The results showed that plant diversity and the content of soil organic matter decreased significantly from NAG to MAG. In total, 29 and 11 phyla bacteria and fungi were detected, respectively. Compared with that in NAG, the Shannon indexes of the bacterial community increased significantly in MAG (from 9.51 to 9.89), whereas these differences were not significant between the NAG and MAG fungal community. The structure and composition of the soil microbial community showed significant differences between NAG and MAG. In addition, Mantel test results suggested that soil total organic matter, total nitrogen, and soil moisture were significantly correlated with variations in the bacterial community, and soil total organic matter and soil moisture were significantly correlated with variations in fungal community. The results of linear discriminant analysis (LEfSe) indicated that Atribacteria and Ascomycota microorganisms could be considered as the indicator groups for NAG, whereas Gemmata and Trichocomaceae microorganisms could be considered as the indicator groups for MAG. Tax4Fun2 results showed that the transition from NAG to MAG affected the utilization of different carbon sources by bacteria.

Cost-Effectiveness Analyses of Digital Health Technology for Improving the Uptake of Vaccination Programs: Systematic Review.

BACKGROUND: Vaccination is the most effective strategy to prevent infectious diseases, yet vaccination coverage has not reached the target level. To promote vaccination uptake, digital health interventions (DHIs) have been used in various vaccination programs. OBJECTIVE: This study aimed to perform a systematic review of the cost-effectiveness analyses of DHIs for the improvement of the uptake of vaccination programs. METHODS: A literature review was conducted in MEDLINE (Ovid), Embase (Ovid), APA PsycINFO (Ovid), Web of Science, Scopus, CINAHL Ultimate (EBSCOhost), Center for Review and Dissemination, and Institute for IEEE Xplore up to October 2022. Health economic evaluations that met the following inclusion criteria were included: (1) adult or pediatric vaccination programs; (2) interventions delivered through digital technology; (3) full-scale health economic analyses including cost-effectiveness, cost-utility, cost-benefit, or cost-consequence analyses; and (4) evaluations conducted by model-based or trial-based analyses. The quality of each included study was evaluated using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). RESULTS: The systematic review included 7 studies. Four of the cost-effectiveness studies were conducted by model-based analyses, and 3 were trial-based analyses. One study reported the additional cost per quality-adjusted life years (QALYs) gained, whereas 6 studies reported the additional cost per individual vaccinated (or return case). The vaccines targeted the human papillomavirus (HPV) vaccine, influenza vaccination, measles-mumps-rubella (MMR) vaccine, and children immunization at different ages. The DHIs were delivered by television campaign, web-based decision aid, SMS text message, telephone, and computer-generated recall letters. The studies were classified as very good (n=5) and good (n=2) qualities. One study concluded that the DHI was cost-saving, and 6 studies concluded that the DHI was cost-effective. CONCLUSIONS: This study is the first systematic review on cost-effectiveness analyses of DHIs to improve vaccination uptake. All included studies have good to very good quality on study assessment and reported the DHIs to be cost-saving or cost-effective in the improvement of vaccination uptake.

Functional dysconnectivity of anterior cingulate subregions in schizophrenia and psychotic and nonpsychotic bipolar disorder.

Aberrant resting-state functional connectivity (FC) of anterior cingulate cortex (ACC) has been implicated in the pathophysiology of schizophrenia and bipolar disorder (BP). This study investigated the subregional FC of ACC across schizophrenia and psychotic (PBP) and nonpsychotic BP (NPBP) and the relationship between brain functional alterations and clinical manifestations. A total of 174 first-episode medication-naive patients with schizophrenia (FES), 80 patients with PBP, 77 patients with NPBP and 173 demographically matched healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. Brain-wide FC of ACC subregions was computed for each individual, and compared between the groups. General intelligence was evaluated using the short version of the Wechsler Adult Intelligence Scale. Relationships between FC and various clinical and cognitive variables were estimated using the skipped correlation. The FES, PBP and NPBP groups showed differing connectivity patterns in the left caudal, dorsal and perigenual ACC. Transdiagnostic dysconnectivity was found in the subregional ACC associated with cortical, limbic, striatal and cerebellar regions. Disorder-specific dysconnectivity in FES was identified between the left perigenual ACC and bilateral orbitofrontal cortex, and the left caudal ACC coupling with the default mode network (DMN) and visual processing region was correlated with psychotic symptoms. In the PBP group, FC between the left dorsal ACC and the right caudate was correlated with psychotic symptoms, and FC connected with the DMN was associated with affective symptoms. The current findings confirmed that subregional ACC dysconnectivity could be a key transdiagnostic feature and associated with differing clinical symptomology across schizophrenia and PBP.

Direct Catalytic Asymmetric and Regiodivergent N1- and C3-Allenylic Alkylation of Indoles.

Herein we report a Pd-catalyzed asymmetric allenylic alkylation strategy for the direct functionalization of 1H-indoles by employing P-chiral BIBOP-type ligands. The regioselectivity (N1/C3) of this process can be switched efficiently. Using Cs2 CO3 at elevated temperatures in MeCN, N1-alkylated indoles bearing axial chirality with a stereocenter non-adjacent (ß) to the nitrogen are produced in good yields with high enantioselectivity and complete N1-regioselectivity regardless of the electronic properties and substitution patterns of diverse indoles. Using K2 CO3 at room temperature in CH2 Cl2 , chiral C3-alkylated indoles can also be obtained. Notably, we introduce a new class of tri-substituted allenylic electrophiles that proceeded through different pathways from di-substituted allenylic electrophiles.

Construction of Acyclic All-Carbon Quaternary Stereocenters and 1,3-Nonadjacent Stereoelements via Organo/Metal Dual Catalyzed Asymmetric Allenylic Substitution of Aldehydes.

A method for the asymmetric construction of functionalized acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements has been developed via organo/metal dual catalyzed asymmetric allenylic substitution of branched and linear aldehydes, by developing an unknown acyclic secondary-secondary diamine as the enabling organocatalyst. Although it is believed that secondary-secondary diamines are difficult to be used as the organocatalysts in organo/metal dual catalysis, this study demonstrates that such diamines can be successfully combined with a metal catalyst in organo/metal dual catalysis. Our study enables the asymmetric construction of two important classes of motifs which were previously difficult to access, axially chiral allene-containing acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements bearing allenyl axial chirality and central chirality, in good yields with high enantio- and diastereoselectivity.

Grass-microbial inter-domain ecological networks associated with alpine grassland productivity.

Associations between grasses and soil microorganisms can strongly influence plant community structures. However, the associations between grass productivity and diversity and soil microbes, as well as the patterns of co-occurrence between grass and microbes remain unclear. Here, we surveyed grass productivity and diversity, determined soil physicochemical, and sequenced soil archaea, bacteria and fungi by metabarcoding technology at 16 alpine grasslands. Using the Distance-decay relationship, Inter-Domain Ecological Network (IDEN), and Mantel tests, we investigated the relationship between grass productivity, diversity and microbial diversity, and the patterns of co-occurrence between grass and microbial inter-domain network in alpine grassland. We found the archaea richness, bacteria richness and Shannon, and fungi α-diversity were significantly negatively correlation with grass diversity, but archaea and bacteria diversity were positively correlation with grass productivity. Moreover, an increase in microbial ß-diversity was observed along with increased discrepancy in grass diversity and productivity and soil variables. Variance partitioning analysis suggested that the contribution of grass productivity on microbial community was higher than that of soil variables and grass diversity, which implies that microbial community was more related to grass productivity. Inter-Domain Ecological Network showed that the grass species formed complex and stable ecological networks with some bacterial, archaeal, and fungal species, and the grass-fungal ecological networks showed the highest robustness, which indicated that soil fungi could better co-coexist with aboveground grass in alpine grasslands. Besides, the connectivity degrees of the grass-microbial network were significantly positively correlated with grass productivity, suggesting that the coexistence pattern of grasses and microbes had a positive feedback effect on the grass productivity. The results are important for establishing the regulatory mechanisms between plants and microorganisms in alpine grassland ecosystems.

Early Efficacy of Antipsychotic Medications at Week 2 Predicts Subsequent Responses at Week 6 in a Large-scale Randomized Controlled Trial.

BACKGROUND: Since the early clinical efficacy of antipsychotics has not yet been well perceived, this study sought to decide whether the efficacy of antipsychotics at week 2 can predict subsequent responses at week 6 and identify how such predictive capacities vary among different antipsychotics and psychotic symptoms. METHODS: A total of 3010 patients with schizophrenia enrolled in a randomized controlled trial (RCT) and received a 6-week treatment with one antipsychotic drug randomly chosen from five atypical antipsychotics (risperidone 2-6 mg/d, olanzapine 5-20 mg/d, quetiapine 400-750 mg/d, aripiprazole 10-30 mg/d, and ziprasidone 80-160 mg/d) and two typical antipsychotics (perphenazine 20-60 mg/d and haloperidol 6-20 mg/d). Early efficacy was defined as the reduction rate using the Positive and Negative Syndrome Scale (PANSS) total score at week 2. With cut-offs at 50% reduction, logistic regression, receiver operating characteristic (ROC) and random forests were adopted. RESULTS: The reduction rate of PANSS total score and improvement of psychotic symptoms at week 2 enabled subsequent responses to 7 antipsychotics to be predicted, in which improvements in delusions, lack of judgment and insight, unusual thought content, and suspiciousness/ persecution were endowed with the greatest weight. CONCLUSION: It is robust enough to clinically predict treatment responses to antipsychotics at week 6 using the reduction rate of PANSS total score and symptom relief at week 2. Psychiatric clinicians had better determine whether to switch the treatment plan by the first 2 weeks.

The Effect of a Long-Term Care Insurance Program on Subjective Well-Being of Older Adults with a Disability: Quasi-Experimental Evidence from China.

China launched its long-term care insurance (LTCI) program for older adults in 2016. Although the scheme has shown some promising outcomes, little is known about whether it improves subjective well-being. This study explored this topic among older persons with a disability and identified the underlying mechanisms associated with the channel of this effect using data from a national survey. The LTCI program was shown to improve the subjective well-being among older persons with a disability and this effect increased over time. The LTCI program has great positive effect among women and those who lived alone compared to their counterparts. Mechanism analysis revealed that the main channel by which the LTCI program has positive effect occurred through the satisfaction of long-term care needs and improved self-reported health. This study suggests promising benefits of the LTCI program for older Chinese adults.

Cost-effectiveness of anlotinib vs. pembrolizumab and nivolumab as third-line treatment in recurrent small cell lung cancer in China.

BACKGROUND: The study aims to evaluate the cost-effectiveness of anlotinib versus pembrolizumab and nivolumab as the third-line treatment in recurrent small cell lung cancer (SCLC) patients from the Chinese healthcare system perspective. RESEARCH DESIGN AND METHODS: A Markov model was built to simulate the costs and health outcomes in the 4-year horizon. Efficacy and safety data of anlotinib, pembrolizumab, and nivolumab in patients with recurrent SCLC were derived from three studies. Cost and utility values were derived from local charges, the published literature, and related databases. Three scenario analyses and sensitivity analyses were performed to explore the robustness of the results. RESULTS: Compared with anlotinib, pembrolizumab and nivolumab were estimated to gain an additional 0.18 and 0.10 quality-adjusted life years (QALYs) at an incremental cost of $10,446 and $5,182, resulting in an increment cost-utility ratio (ICUR) of $58,221/QALY and $56,733/QALY. The sensitivity analyses showed that the likelihood of anlotinib being cost-effective was 87.5% to 99.9% at a willingness-to-pay (WTP) threshold of $11,144 to $33,431/QALY. The scenario analyses indicated that the results varied in different scenarios. CONCLUSIONS: The findings suggest that anlotinib could be the most cost-effective option versus pembrolizumab and nivolumab in the third-line treatment of recurrent SCLC from the Chinese healthcare system perspective.

Cropland nitrous oxide emissions exceed the emissions of RCP 2.6: A global spatial analysis.

Nitrous oxide (N2O), as a potent greenhouse gas, must be limited to prevent the global temperature increasing by >2 °C. Cropland is the largest source of anthropogenic N2O emissions; however, earlier estimates for emissions and their exceedances still remain uncertainties. Here, we used a spatially explicit model to estimate cropland N2O emission in 2014 by refined grid-level crop-specific EFs and considered the background emission. We also sought to determine where N2O emissions exceed the "boundary" through analysis of spatial data from representative concentration pathway (RCP) 2.6. The global cropland N2O emission was 2.92 ± 0.59 Tg N yr-1, which far exceeds the 0.82 Tg N yr-1 boundary, over 90 % of cropland areas exceeded the boundary. Western Europe, Southeastern China, Pakistan, and the Ganges Plain exceeded the boundary by >2 kg N ha-1 yr-1. The boundary exceedances showed a positive linear response with respect to total cropland emission and a quadratic response to GDP per capita at the country level. Our study highlights the necessity of accurate estimations of spatial variations in cropland N2O emissions and evaluation of exceedances, to facilitate the development of more effective mitigation measures in different regions.

Does the provision of informal care matter for caregivers' mental health? Evidence from China.

This paper investigates the causal effect of informal care on the mental health of caregivers and disentangles the mechanisms of such effect. Using 2011-2018 CHARLS data, the fixed effects and instrumental variable approaches was conducted to address fundamental endogeneity problems. This study found that there was no impact of informal caregiving on caregivers' mental health in general. However, the intensity of caregiving was shown to negatively impair mental health. The impact of informal caregiving varied by kinship, cultural context, and residential area. Participation in social and exercise activities and life satisfaction mediated the association between the provision of informal care and caregivers' mental health. Long-term care insurance and the provision of formal care substantially modified the negative impacts of informal caregiving.

Economic evaluation of sintilimab plus chemotherapy vs. pembrolizumab plus chemotherapy for the treatment of first-line advanced or metastatic squamous NSCLC.

Background and objective: Sintilimab has superior efficacy and safety in patients with advanced or metastatic squamous non-small cell lung cancer (NSCLC), but its cost-effectiveness in China is unclear. This study is to evaluate the cost-effectiveness of sintilimab plus chemotherapy vs. pembrolizumab plus chemotherapy for locally advanced or metastatic squamous NSCLC in China. Methods: From the perspective of the Chinese health system, the partitioned survival model with three health states was established in a 3-week cycle and a lifetime time horizon. The two-stage method was used to estimate the overall survival hazard ratios to avoid the bias by crossover design in ORIENT-12 and KEYNOTE-407 studies. The anchored matching adjusted indirect comparison method (MAIC) was used for indirect comparison based on the individual patient data from ORIENT-12 and the publicly published KEYNOTE-407 study due to the lack of head-to-head clinical trials. Only direct medical costs were included, and utilities were derived from the published literature in the base case analysis. Sensitivity analysis was also performed to verify the robustness of the model results. In addition, the scenario analysis where the utilities were derived from the Quality of Life Questionnaire-Core 30 (QLQ-C30) scale in the ORIENT-12 by mapping to the EuroQol-5-dimension 5-level (EQ-5D-5L) was carried out to explore the uncertainty of the results. Results: Compared with pembrolizumab + chemotherapy, sintilimab + chemotherapy incurred a lower lifetime cost ($12,321 vs. 36,371) and yielded fewer quality-adjusted life-years (QALYs) (0.9902 vs. 1.0085), which resulted in an incremental cost-effectiveness ratio (ICER) of $1,314,208/QALY. A sintilimab strategy is a cost-effectiveness option under the WTP of 1-3 times the GDP per capita in China ($11,250/QALY~$33,749/QALY). The utility value of the post-progression, the unit cost of albumin paclitaxel, and the utility value of the progression-free state were the main drivers in the deterministic sensitivity analysis (DSA). According to the probabilistic sensitivity analysis (PSA), sintilimab + chemotherapy was 100% cost-effective when the WTP was 1-3 times China's per capita GDP. The results of the scenario analysis showed that sintilimab + chemotherapy obtained more QALYs (1.2319 vs. 1.1815) and lower costs ($12,321 vs. 36,371), which implied that sintilimab + chemotherapy may dominate the pembrolizumab + chemotherapy. Conclusion: Compared with pembrolizumab + chemotherapy, sintilimab + chemotherapy is more cost-effective for first-line treatment in Chinese patients with locally advanced or metastatic squamous NSCLC.

Application of Organic Fertilizer Changes the Rhizosphere Microbial Communities of a Gramineous Grass on Qinghai-Tibet Plateau.

The effects of organic fertilizer application on the soil microbial community in grassland systems have been extensively studied. However, the effects of organic fertilizers on the structure of rhizosphere microbial communities are still limited. In this study, the diversity and composition of rhizosphere microbial communities of a gramineous grass Elymus nutans under organic fertilizer treatment were studied in an artificial pasture on Qinghai-Tibet Plateau. After a growing season, the application of organic fertilizer not only increased the height and biomass of Elymus nutans, but also changed the rhizosphere microbial compositions. In particular, organic fertilizer increased the diversity of rhizosphere bacterial community and inhibited the growth of pathogenic bacteria such as Acinetobacter, but the opposite trend was observed for the diversity of fungal community. The assembly process of fungal community was changed from a stochastic process to a deterministic process, indicating that selection was strengthened. Additionally, both the infection rate of arbuscular mycorrhizal fungi (AMF) toward host plants and the development of AMF-related structures were significantly increased after the application of organic fertilizer. Our study demonstrated that the addition of organic fertilizer to artificial pasture could improve the growth of grass through the alteration of the rhizosphere microbial communities. Organic fertilizer had a greater selectivity for the bacterial and the fungal communities that enhanced the niche filtration in this community, further benefiting the yield of forages.

Generation and characterization of human-derived iPSC lines from two cousins with schizophrenia and bipolar disorder and their unaffected cousin.

Schizophrenia (SCZ) and bipolar disorder (BD) are debilitating neurodevelopmental disorders with high heritability. In this study, peripheral blood mononuclear cells (PBMCs) were donated by three females. An adolescent female was clinically diagnosed as first-episode SCZ. One of her cousins was clinically diagnosed as BD and another one was unaffected control. Induced pluripotent stem cells (iPSCs) were established with reprograming factors Oct4, Sox2, Nanog, Lin28, c-myc, Klf4, and SV40LT. All lines presented normal karyotype and highly expressed pluripotency markers in vitro. All iPSCs were capable to differentiate into derivatives of three germ layers in vivo.