Evaluation of modified clear Twin Block aligner in treating adolescents with skeletal class II malocclusion: A two-centre cephalometric study.

INTRODUCTION: The purpose of this study was to evaluate the therapeutic effect of modified clear Twin Block (CTB) aligner and traditional twin block (TB) appliance from skeletal, dentoalveolar and soft tissue changes in adolescents with skeletal class II malocclusion. METHODS: A total of 80 adolescents, included in this study from two medical centres, were distributed into CTB group, TB group and control group based on the treatment they received. Lateral cephalograms at pre-treatment (T1) and post-treatment (T2) were measured by modified Pancherz's cephalometric analysis, and dentoskeletal and soft tissue changes were analysed by independent-sample t-test, paired-sample t-test, ANOVA test and Scheffe's Post Hoc test. RESULTS: Seventy-five adolescents completed the study, including 32 in the CTB group, 32 in the TB group and 11 in the control group. Both CTB and TB treatment showed significant differences in most dentoskeletal and soft tissue measurements. Compared with the control group, improvements were observed in class II molar relationship through significant different in S Vert/Ms-S Vert/Mi in the CTB group (P < .01) and the TB group (P < .001), as well as deep overjet through significant different in S Vert/Is-S Vert/Ii in the CTB group (P < .001) and the TB group (P < .001). Besides, the CTB group also showed less protrusion of lower incisors and resulted in a more significant improvement in profile with fewer adverse effects on speaking, eating and social activities. CONCLUSIONS: For adolescents with skeletal class II malocclusion, CTB appliance was as effective as TB on improving dentoskeletal and soft tissue measurements, featuring more reliable teeth control and patient acceptance.

Effects of aerobic exercise on children's executive function and academic performance: A systematic review and meta-analysis.

Objective: To investigate the effects of exercise on executive function in children, providing an evidence-based foundation to inform future research in school physical education and health education. Methods: We searched ten databases: Cochrane Library, Scopus, OVID, Web of Science, PubMed, EBSCOhost, SPORTDiscus, PsycINFO, CNKI, WANFANG DATA, VIP, and SinoMed, and eight articles were included. Applying the revised Cochrane Risk of Bias Tool for Randomized Trials (RoB2), funnel plots and Egger regression analysis were integrated with R meta-analysis to screen for publication bias. The quality of the evidence was appraised using the Grading system. Results: The included literature contained 2655 participants, with 1308 in the experimental group and 1347 in the control group. The results indicated that the aerobic exercise group considerably improved inhibitory control in children compared to the control group [SMD = 0.29, 95% CI (0.05, 0.54), P = 0.018]; working memory [SMD = 0.25, 95% CI (0.07, 0.42), P = 0.005]; and cognitive flexibility [SMD = 0.36, 95% CI (0.17, 0.54), P < 0.001]. However, the findings indicated that only aerobic exercise interventions extending beyond 50 weeks positively influenced academic performance in children [SMD = 1.19, 95% CI (0.34, 2.04), P = 0.006]. The results of an Egger regression analysis revealed that the p-values for inhibitory control, working memory, cognitive flexibility, and academic performance were more significant than 0.1. The Grade system said that the quality of evidence was all low regarding the level of evidence. Conclusion: Aerobic exercise enhanced executive function but only aerobic exercise interventions extending beyond 50 weeks demonstrated a significant effect on the academic performance of children. Due to the low quality of evidence presented in this study, additional high-quality randomized controlled trials are needed to confirm these findings.

The hidden risk: Changes in functional potentials of microbial keystone taxa under global climate change jeopardizing soil carbon storage in alpine grasslands.

Climate change is endangering the soil carbon stock of alpine grasslands on the Qinghai-Tibetan Plateau (QTP), but the limited comprehension regarding the mechanisms that sustain carbon storage under hydrothermal changes increases the uncertainty associated with this finding. Here, we examined the relative abundance of soil microbial keystone taxa and their functional potentials, as well as their influence on soil carbon storage with increased precipitation across alpine grasslands on the QTP, China. The findings indicate that alterations in precipitation significantly decreased the relative abundance of the carbon degradation potentials of keystone taxa, such as chemoheterotrophs. The inclusion of keystone taxa and their internal functional potentials in the two best alternative models explained 70% and 63% of the variance in soil organic carbon (SOC) density, respectively. Moreover, we found that changes in chemoheterotrophs had negative effects on SOC density as indicated by a structural equation model, suggesting that some specialized functional potentials of keystone taxa are not conducive to the accumulation of carbon sink. Our study offers valuable insights into the intricate correlation between precipitation-induced alterations in soil microbial keystone taxa and SOC storage, highlighting a rough categorization is difficult to distinguish the hidden threats and the importance of incorporating functional potentials in SOC storage prediction models in response to changing climate.

SP-CHAP, an endolysin with enhanced activity against biofilm pneumococci and nasopharyngeal colonization.

Streptococcus pneumoniae (Spn), a Gram-positive bacterium, is responsible for causing a wide variety of invasive infections. The emergence of multi-drug antibiotic resistance has prompted the search for antimicrobial alternatives. Phage-derived peptidoglycan hydrolases, known as endolysins, are an attractive alternative. In this study, an endolysin active against Spn, designated SP-CHAP, was cloned, produced, purified, biochemically characterized, and evaluated for its antimicrobial properties. Cysteine, histidine-dependent amidohydrolase/peptidase (CHAP) domains are widely represented in bacteriophage endolysins but have never previously been reported for pneumococcal endolysins. Here, we characterize the first pneumococcal endolysin with a CHAP catalytic domain. SP-CHAP was antimicrobial against all Spn serovars tested, including capsular and capsule-free pneumococci, and it was found to be more active than the most widely studied pneumococcal endolysin, Cpl-1, while not affecting various oral or nasal commensal organisms tested. SP-CHAP was also effective in eradicating Spn biofilms at concentrations as low as 1.56 µg/mL. In addition, a Spn mouse nasopharyngeal colonization model was employed, which showed that SP-CHAP caused a significant reduction in Spn colony-forming units, even more than Cpl-1. These results indicate that SP-CHAP may represent a promising alternative to combating Spn infections. IMPORTANCE: Considering the high rates of pneumococcal resistance reported for several antibiotics, alternatives are urgently needed. In the present study, we report a Streptococcus pneumoniae-targeting endolysin with even greater activity than Cpl-1, the most characterized pneumococcal endolysin to date. We have employed a combination of biochemical and microbiological assays to assess the stability and lytic potential of SP-CHAP and demonstrate its efficacy on pneumococcal biofilms in vitro and in an in vivo mouse model of colonization. Our findings highlight the therapeutic potential of SP-CHAP as an antibiotic alternative to treat Streptococcus pneumoniae infections.

Relationships between functional temporomandibular joint space and disc morphology, position, and condylar osseous condition in patients with temporomandibular disorder.

OBJECTIVE: To investigate the correlations between joint space and temporomandibular joint (TMJ) components and the compressive states of the disc and condyle subsequent to joint space changes. MATERIALS AND METHODS: A total of 240 TMJs were categorized according to disc morphology, disc position, and condylar osseous condition. The two-dimensional (2D) and three-dimensional (3D) measurements were compared. The functional joint space (FJS) and disc areas on closed- and open-mouth images (DA-C and DA-O) were also calculated, and the joint space was measured in five directions. Different groups of TMJ components were compared. A spring model was used to simulate the effect of condylar displacement on the disc and condyle. RESULTS: Disc morphology was strongly correlated with its position. The measurements were equivalent between 2D and 3D methods. DA-C and FJS differed significantly between groups. The DA-C to FJS ratio differed between the Class 2 and Class 3 groups and between disc displacement groups with and without reduction. Altered disc morphology and position were correlated with significant changes in joint space in the 60°, 90°, and 120° directions. Despite minor discrepancies among condylar osseous conditions, reduced joint space was correlated with bone destruction at the corresponding site. The spring model stimulation revealed that condylar displacement caused elevated stresses on the disc and condyle. CONCLUSIONS: Condylar displacement causes joint space alterations while exerting compressive pressure on both the disc and condyle. CLINICAL RELEVANCE: Proper condylar positioning within the fossa is recommended to ensure sufficient articular disc accommodation.

Efficacy and Safety Assessment of Intrathoracic Perfusion Chemotherapy Combined with immunological factor Interleukin-2 in the Treatment of Advanced Non-Small Cell Lung Cancer: A Retrospective Cohort Study.

Objective: This study evaluated the efficacy and safety of the gemcitabine and oxaliplatin intrathoracic perfusion chemotherapy (IPCGOR) regimen combined with interleukin-2 (IL-2) for advanced non-small cell lung cancer (NSCLC). Methods: We conducted a retrospective analysis of 460 advanced NSCLC patients from the Yunnan Province Early Cancer Diagnosis and Treatment Project (June 2020-October 2022), assessing the IPCGOR and IL-2 combination. Outcomes were measured based on RECIST 1.1 criteria, focusing on objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (MOS), and treatment safety. Results: The treatment demonstrated an ORR of 67.4%, a DCR of 97.4%, an mPFS of 8.5 months, and an MOS of 12.5 months. 14 patients underwent successful surgery post-treatment. Common adverse reactions were manageable, with no treatment-related deaths reported. Conclusion: The IPCGOR combined with IL-2 regimen shows promising efficacy and a tolerable safety profile for advanced NSCLC. These findings suggest its potential as a reference for treating advanced NSCLC. However, the study's retrospective nature and single-center design pose limitations. Future research should focus on prospective studies, randomized controlled trials, and long-term outcome assessments, particularly in diverse patient subgroups, to further validate and refine the clinical application of this regimen.

A Girl with PRRT2 Mutation Presenting with Benign Familial Infantile Seizures Followed by Autistic Regression.

Benign familial infantile seizure (BFIS) is an autosomal dominant infantile-onset epilepsy syndrome with a typically benign prognosis. It is commonly associated with heterozygous mutations of the PRRT2 gene located on chromosome 16p11.2. The frameshift heterozygous mutation (c.649dupC, p.Arg217Profs∗8) in PRRT2 is responsible for the majority of BFIS cases. In this report, we present a rare case of a girl with a confirmed clinical and genetic diagnosis of BFIS due to a frameshift heterozygous mutation in PRRT2 (c.649dupC). She exhibited typical neurodevelopment until 15 months of age, followed by an unexpected severe autistic regression. In addition to BFIS, PRRT2 mutations are also associated with paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions and paroxysmal choreoathetosis (ICCA), indicating a complex genotype-phenotype heterogeneity in PRRT2 mutations. This clinical observation highlights the possibility that BFIS patients with PRRT2 mutations may not always have a benign neurodevelopmental prognosis, emphasizing the need for long-term clinical follow-up.

Screening and Bioinformatics Analysis of Differential Genes in Autism Spectrum Disorder Based on GEO Database.

OBJECTIVE: The prevalence of autism spectrum disorder (ASD) in children has been increasing year by year, which has seriously affected the quality of life of children. There are many theories about the cause of ASDs, with some studies suggesting that it may be related to gene expression levels or inflammation and immune system dysfunction. But the exact mechanism is not fully understood. METHODS: profile of gene expression The protein interaction network (PPI) of differentially expressed genes was created using the STRING web tool and GSE77103, which was chosen from the gene expression omnibus (GEO) database. Using the CytoHubba plugin of Cytoscape program, the hub genes were examined. The hub gene regulatory network for miRNA-mRNA was then built. RESULTS: We identified 551 differentially expressed genes(DEGs) in 8 children with ASD and normal children. In addition, we screened out 10 hub genes (MX1, ISG15, IRF7, DDX58, IFIT1, BCL2L1, HPGDS, CTSD, PTGS2 and CD68) that were most associated with the development of ASDs. Then, microRNAs (miRNAs) closely related to hub genes (such as has-miR-27a-5p) were screened, and the miRNA-mRNA regulatory network was constructed. CONCLUSION: In this study, a total of 10 hub genes were identified, including MX1, ISG15, IRF7, DDX58, IFIT1, BCL2L1, HPGDS, CTSD, PTGS2 and CD68, which are closely related to ASD. These genes may play a key role in the occurrence and progression of ASD. In addition, we also revealed some miRNAs that regulate the hub genes of ASD. These results may deepen our understanding of ASD and provide potential biomarkers and targets for future treatment of patients with ASD.

Anaphylatoxin signaling activates macrophages to control intracellular Rickettsia proliferation.

IMPORTANCE: Pathogenic Rickettsia species are extremely dangerous bacteria that grow within the cytoplasm of host mammalian cells. In most cases, these bacteria are able to overpower the host cell and grow within the protected environment of the cytoplasm. However, a dramatic conflict occurs when Rickettsia encounter innate immune cells; the bacteria can "win" by taking over the host, or the bacteria can "lose" if the host cell efficiently fights the infection. This manuscript examines how the immune complement system is able to detect the presence of Rickettsia and alert nearby cells. Byproducts of complement activation called anaphylatoxins are signals that "activate" innate immune cells to mount an aggressive defensive strategy. This study enhances our collective understanding of the innate immune reaction to intracellular bacteria and will contribute to future efforts at controlling these dangerous infections.

Framework for determining the optimal course of action when efficiency and affordability measures differ by perspective in cost-effectiveness analysis-with an illustrative case of HIV treatment in Mozambique.

BACKGROUND: Cost-effectiveness analysis (CEA) is a standard tool for evaluating health programs and informing decisions about resource allocation and prioritization. Most CEAs evaluating health interventions in low- and middle-income countries adopt a health sector perspective, accounting for resources funded by international donors and country governments, while often excluding out-of-pocket expenditures and time costs borne by program beneficiaries. Even when patients' costs are included, a companion analysis focused on the patient perspective is rarely performed. We view this as a missed opportunity. METHODS: We developed methods for assessing intervention affordability and evaluating whether optimal interventions from the health sector perspective also represent efficient and affordable options for patients. We mapped the five different patterns that a comparison of the perspective results can yield into a practical framework, and we provided guidance for researchers and decision-makers on how to use results from multiple perspectives. To illustrate the methodology, we conducted a CEA of six HIV treatment delivery models in Mozambique. We conducted a Monte Carlo microsimulation with probabilistic sensitivity analysis from both patient and health sector perspectives, generating incremental cost-effectiveness ratios for the treatment approaches. We also calculated annualized patient costs for the treatment approaches, comparing the costs with an affordability threshold. We then compared the cost-effectiveness and affordability results from the two perspectives using the framework we developed. RESULTS: In this case, the two perspectives did not produce a shared optimal approach for HIV treatment at the willingness-to-pay threshold of 0.3 × Mozambique's annual GDP per capita per DALY averted. However, the clinical 6-month antiretroviral drug distribution strategy, which is optimal from the health sector perspective, is efficient and affordable from the patient perspective. All treatment approaches, except clinical 1-month distributions of antiretroviral drugs which were standard before Covid-19, had an annual cost to patients less than the country's annual average for out-of-pocket health expenditures. CONCLUSION: Including a patient perspective in CEAs and explicitly considering affordability offers decision-makers additional insights either by confirming that the optimal strategy from the health sector perspective is also efficient and affordable from the patient perspective or by identifying incongruencies in value or affordability that could affect patient participation.

Divergent sequences of tetraspanins enable plants to specifically recognize microbe-derived extracellular vesicles.

Extracellular vesicles (EVs) are important for cell-to-cell communication in animals. EVs also play important roles in plant-microbe interactions, but the underlying mechanisms remain elusive. Here, proteomic analyses of EVs from the soybean (Glycine max) root rot pathogen Phytophthora sojae identify the tetraspanin family proteins PsTET1 and PsTET3, which are recognized by Nicotiana benthamiana to trigger plant immune responses. Both proteins are required for the full virulence of P. sojae. The large extracellular loop (EC2) of PsTET3 is the key region recognized by N. benthamiana and soybean cells in a plant receptor-like kinase NbSERK3a/b dependent manner. TET proteins from oomycete and fungal plant pathogens are recognized by N. benthamiana thus inducing immune responses, whereas plant-derived TET proteins are not due to the sequence divergence of sixteen amino acids at the C-terminal of EC2. This feature allows plants to distinguish self and non-self EVs to trigger active defense responses against pathogenic eukaryotes.

Identification of target hub genes and construction of a novel miRNA regulatory network in autism spectrum disorder by integrated analysis.

The incidence of autism spectrum disorder (ASD) is increasing year by year in children. The aim of the study was to find possible biomarkers for ASD diagnosis as well as examine MicroRNA (miRNA) signatures and crucial pathways. We conducted a two-stage study to explore potential target genes and functional miRNAs. Peripheral blood samples of children with ASD were enrolled and performed RNA sequencing analysis. The overlapped candidate genes were further screened in combination with differentially expressed genes (DEGs) of GSE77103 datasets. STRING established a protein-protein interaction network comprising DEGs. The hub genes were filtered out using the CytoHubba. Then, we set up a miRNA-mRNA regulatory network. Correlational analyses between hub genes and immune cells associated with ASD were carried out using the CIBERSORT software to assess the diversity of immune cell types in ASD. RNA-sequencing analysis was used to confirm the differential expression of 3 hub genes. Briefly, after blood samples were sequenced interrogating 867 differential genes in our internal screening dataset. After screening GEO databases, 551 DEGs obtained from GSE77103. Fourteen common genes were overlapped through DEGs of GEO datasets and internal screening dataset. Among protein-protein interaction network, 10 hub genes with high degree algorithm were screened out and 3 hub genes of them - ADIPOR1, LGALS3, and GZMB - that were thought to be most associated with the emergence of ASD. Then, we developed a network of miRNA-mRNA regulatory interactions by screening miRNAs (such as hsa-miR-20b-5p, hsa-miR-17-5p, and hsa-miR-216b-5p) that were closely associated to 3 hub genes. Additionally, we discovered 18 different immune cell types associated with ASD using the CIBERSORT algorithm, and we discovered that mononuclear macrophages differed considerably between the 2 groups. Overall, 3 hub genes (ADIPOR1, LGALS3, and GZMB) and 15 candidates miRNAs-target 3 genes regulatory pathways representing potentially novel biomarkers of ASD diseases were revealed. These findings could enhance our knowledge of ASD and offer possible therapeutic targets of ASD patients in the future.

Exploring the molecular mechanism of comorbidity of autism spectrum disorder and inflammatory bowel disease by combining multiple data sets.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is difficult to diagnose. Inflammatory bowel disease (IBD) is a common chronic digestive disease. Previous studies have shown a potential correlation between ASD and IBD, but the pathophysiological mechanism remains unclear. The purpose of this research was to examine the biological mechanisms underlying the differentially expressed genes (DEGs) of ASD and IBD using bioinformatics tools. METHODS: Limma software was used to evaluate the DEGs between ASD and IBD. The GSE3365, GSE18123, and GSE150115 microarray data sets were acquired from the Gene Expression Omnibus (GEO) database. We then performed 6 analyses, namely, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotation; weighted gene coexpression network analysis; correlation analysis of hub genes with autophagy, ferroptosis and immunity; transcriptional regulation analysis of hub genes; single-cell sequencing analysis; and potential therapeutic drug prediction. RESULTS: A total of 505 DEGs associated with ASD and 616 DEGs associated with IBD were identified, and 7 genes overlapped between these sets. GO and KEGG analyses revealed several pathways enriched in both diseases. A total of 98 common genes related to ASD and IBD were identified by weighted gene coexpression network analysis (WGCNA), and 4 hub genes were obtained by intersection with the 7 intersecting DEGs, which were PDGFC, CA2, GUCY1B3 and SDPR. We also found that 4 hub genes in the two diseases were related to autophagy, ferroptosis or immune factors. In addition, motif-TF annotation analysis showed that cisbp__M0080 was the most relevant motif. We also used the Connectivity Map (CMap) database to identify 4 potential therapeutic agents. CONCLUSION: This research reveals the shared pathogenesis of ASD and IBD. In the future, these common hub genes may provide new targets for further mechanistic research as well as new therapies for patients with ASD and IBD.

Prioritizing Quality Measures in Acute Stroke Care : A Cost-Effectiveness Analysis.

BACKGROUND: The American Heart Association and American Stroke Association (AHA/ASA) endorsed 15 process measures for acute ischemic stroke (AIS) to improve the quality of care. Identifying the highest-value measures could reduce the administrative burden of quality measure adoption while retaining much of the value of quality improvement. OBJECTIVE: To prioritize AHA/ASA-endorsed quality measures for AIS on the basis of health impact and cost-effectiveness. DESIGN: Individual-based stroke simulation model. DATA SOURCES: Published literature. TARGET POPULATION: U.S. patients with incident AIS. TIME HORIZON: Lifetime. PERSPECTIVE: Health care sector. INTERVENTION: Current versus complete (100%) implementation at the population level of quality measures endorsed by the AHA/ASA with sufficient clinical evidence (10 of 15). OUTCOME MEASURES: Life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios, and incremental net health benefits. RESULTS OF BASE-CASE ANALYSIS: Discounted life-years gained from complete implementation would range from 472 (tobacco use counseling) to 34 688 (early carotid imaging) for an annual AIS patient cohort. All AIS quality measures were cost-saving or highly cost-effective by AHA standards (<$50 000 per QALY for high-value care). Early carotid imaging and intravenous tissue plasminogen activator contributed the largest fraction of the total potential value of quality improvement (measured as incremental net health benefit), accounting for 72% of the total value. The top 5 quality measures accounted for 92% of the total potential value. RESULTS OF SENSITIVITY ANALYSIS: A web-based user interface allows for context-specific sensitivity and scenario analyses. LIMITATION: Correlations between quality measures were not incorporated. CONCLUSION: Substantial variation exists in the potential net benefit of quality improvement across AIS quality measures. Benefits were highly concentrated among 5 of 10 measures assessed. Our results can help providers and payers set priorities for quality improvement efforts and value-based payments in AIS care. PRIMARY FUNDING SOURCE: National Institute of Neurological Disorders and Stroke.

Molecular glue CELMoD compounds are regulators of cereblon conformation.

Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo-electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)-CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.

Re-evaluating the health impact and cost-effectiveness of tuberculosis preventive treatment for modern HIV cohorts on antiretroviral therapy: a modelling analysis using data from Tanzania.

BACKGROUND: Isoniazid preventive therapy (IPT) can prevent tuberculosis among people receiving antiretroviral therapy (ART). HIV programmes are now initiating patients on ART with higher average CD4 cell counts and lower tuberculosis risks under test-and-treat guidelines. We aimed to investigate how this change has affected the health impact and cost-effectiveness of IPT. METHODS: We constructed a tuberculosis-HIV microsimulation model parameterised using data from a large HIV treatment programme in Dar es Salaam, Tanzania. We simulated long-term health and cost outcomes for the 211 748 individuals initiating ART between Jan 1, 2014, and Dec 31, 2020, under three scenarios: no IPT access; observed levels of IPT access (75%) and completion (71%); and full (100%) IPT access and completion. We stratified results by ART initiation year and starting CD4 cell count. FINDINGS: Observed levels of IPT access were estimated to have averted 12 800 (95% uncertainty interval 7300 to 21 600) disability-adjusted life-years (DALYs) and saved US$23 000 (-2 268 000 to 1 388 000). Full IPT access would have averted 24 500 (15 100 to 38 300) DALYs and cost $825 000 (-1 594 000 to 4 751 000), equivalent to $23·4 per DALY averted. Lifetime health benefits of IPT were estimated to be greater for more recent ART cohorts, while lifetime costs were stable. In subgroup analyses, a higher CD4 cell count at ART initiation was associated with greater health gains from IPT (15 900 [10 300 to 22 500] DALYs averted by full IPT per 100 000 patients for CD4 count >500 cells per µL at ART initiation, versus 7400 [4500 to 11 600] for CD4 count <100 cells per µL) and lower incremental lifetime costs. INTERPRETATION: IPT remains highly cost-effective or cost-saving for recent ART cohorts. The health impact and cost-effectiveness of IPT are estimated to improve as patients initiate ART earlier in the course of infection. FUNDING: US National Institutes of Health.

Microbe-derived non-necrotic glycoside hydrolase family 12 proteins act as immunogenic signatures triggering plant defenses.

Plant pattern recognition receptors (PRRs) are sentinels at the cell surface sensing microbial invasion and activating innate immune responses. During infection, certain microbial apoplastic effectors can be recognized by plant PRRs, culminating in immune responses accompanied by cell death. However, the intricated relationships between the activation of immune responses and cell death are unclear. Here, we studied the glycoside hydrolase family 12 (GH12) protein, Ps109281, secreted by Phytophthora sojae into the plant apoplast during infection. Ps109281 exhibits xyloglucanase activity, and promotes P. sojae infection in a manner dependent on the enzyme activity. Ps109281 is recognized by the membrane-localized receptor-like protein RXEG1 and triggers immune responses in various plant species. Unlike other characterized GH12 members, Ps109281 fails to trigger cell death in plants. The loss of cell death induction activity is closely linked to a sequence polymorphism at the N-terminus. This sequence polymorphism does not affect the in planta interaction of Ps109281 with the recognition receptor RXEG1, indicating that cell death and immune response activation are determined using different regions of the GH12 proteins. Such GH12 protein also exists in other Phytophthora and fungal pathogens. Taken together, these results unravel the evolution of effector sequences underpinning different immune outputs.

Trends in Author-Reported Cost-Effectiveness Thresholds in the United States from 1995 to 2018: Implications for Discount Rates.

BACKGROUND: Decisions based on cost-effectiveness analyses (CEAs) using equal discount rates for health and cost outcomes are consistent with using a constant cost-effectiveness threshold over time. We sought to analyze trends in author-reported cost per quality-adjusted life-year (QALY) thresholds from CEAs published for the US setting over 24 y to retrospectively assess whether the recommended equal discount rates for costs and health were consistent with trends in the CEA literature. METHODS: We used the Tufts CEA Registry to assess whether author-reported cost-effectiveness thresholds changed in CEAs published for the US setting between 1995 and 2018 and back-calculated the implied discount rate for health based on these trends for inflation-adjusted cost-effectiveness thresholds and an annual discount rate for costs of 3%. RESULTS: We found 1995 CEAs published for the US setting and found that average nominal and inflation-adjusted cost-effectiveness thresholds increased over that time period. The discount rate for health would need to equal 2.43% to 2.48% (depending on the subset of CEAs analyzed) to be consistent with the observed trends in inflation-adjusted author-reported cost-effectiveness thresholds. We also found that restricting our analysis to currency years between 1995 and 2014 would result in a back-calculated discount rate for health of 2.99% to 3.28%. CONCLUSIONS: We found that CEA researchers have implicitly assumed that inflation-adjusted cost-effectiveness thresholds in the United States have been increasing over time (1995-2018), which is inconsistent with the recommended and prevailing choice of equal discount rates for health and cost outcomes. Our results are sensitive to the cutoff year used in the analysis. HIGHLIGHTS: We show visually and through equations that the recommended and prevailing practice of using equal discount rates for cost and health outcomes in cost-effectiveness analyses (CEAs) logically implies a constant inflation-adjusted cost-effectiveness threshold over time.Using data from the Tufts CEA Registry, we found that author-reported cost-effectiveness thresholds used in CEAs published for the US setting with currency years between 1995 and 2018 increased over time (both with and without adjustment for inflation).Assuming an annual discount rate for costs equal to 3%, the discount rate for health would need to equal approximately 2.5% to preserve consistency across decisions taken at different dates given the observed trends in inflation-adjusted author-reported cost-effectiveness thresholds.This finding depends on the cutoff year used in the analysis (data from currency years 1995-2014 would support use of equal discount rates, whereas data after 2014 would suggest a sharper trend toward increasing cost-effectiveness thresholds).