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Summary The cost-effectiveness of a less intensive fracture liaison service is unknown. We evaluated a fracture liaison service that had been educating and referring patients for secondary prevention of osteoporotic fractures for 6 years. Our results suggest that a less intensive fracture liaison service, with moderate effectiveness, can still be worthwhile. Introduction Fragility fractures are common among older patients; the risk of re-fracture is high but could be reduced with treatments; different versions of fracture liaison service have emerged to reduce recurrent osteoporotic fractures. But the cost-effectiveness of a less intensive model is unknown. The objective of this study was to assess the cost-effectiveness of the Ontario Fracture Clinic Screening program, a fracture liaison service that had been educating and referring fragility fracture patients across Ontario, Canada to receive bone mineral density testing and osteoporosis treatments since 2007. Methods We developed a Markov model to assess the cost-effectiveness of the program over the patients’ remaining lifetime, using rates of bone mineral density testing and osteoporosis treatment and cost of intervention from the program, and supplemented it with the published literature. The analysis took the perspective of a third-party health-care payer. Costs and benefits were discounted at 5 % per year. Sensitivity analyses assessed the effects of different assumptions on the results. Results The program improved quality-adjusted life-years (QALYs) by 4.3 years and led to increased costs of CAD $83,000 for every 1000 patients screened, at a cost of $19,132 per QALY gained. The enhanced model, the Bone Mineral Density (BMD) Fast Track program that includes ordering bone mineral density testing, was even more cost-effective ($5720 per QALY gained). Conclusions The Ontario Fracture Clinic Screening program appears to be a cost-effective way to reduce recurrent osteoporotic fractures.

Fetal growth restriction (FGR) affects up to 5 % of pregnancies worldwide, and trophoblast function plays a significant role on the outcome. An epidemiological study has linked vitamin D deficiency to adverse perinatal outcomes, which include decreased birth weight. The placenta as an important source of vitamin D regulates its metabolism through the vitamin D receptor (VDR), but the mechanism by which VDR regulates trophoblast function is poorly understood. Our study aimed at determining placental VDR expression in FGR and gestation-matched control (GMC) pregnancies and identifying the actions of VDR in trophoblast differentiation and apoptosis. Placentae were collected from a well-defined cohort of idiopathic FGR and GMC pregnancies. VDR mRNA and protein expressions were determined by PCR, immunohistochemistry and immunoblotting, while functional consequences of VDR inactivation in vitro were determined on BeWo cells by determining changes in differentiation, attachment and apoptosis. Significant decreases in VDR mRNA expression ( p  = 0.0005) and protein expression ( p  = 0.0003) were observed in the FGR samples, while VDR inactivation, which showed markers for differentiation, cell attachment and apoptosis, was significantly increased. Thus, decreased placental VDR may contribute to uncontrolled premature differentiation and apoptosis of trophoblasts that are characteristics of idiopathic FGR pregnancies. Key message Fetal growth restriction (FGR) affects up to 5 % of all pregnancies worldwide. FGR is the second highest cause of perinatal mortality and morbidity. The placenta plays a pivotal role in vitamin D metabolism during pregnancy. Vitamin D deficiency is associated with adverse pregnancy outcomes. Placental vitamin D receptor expression is decreased in FGR.

Objective Based on programs implemented in 2011–2013 in three Canadian provinces to improve the support paramedics provide to people receiving palliative care, the Canadian Partnership Against Cancer and Healthcare Excellence Canada provided support and funding from 2018 to 2022 to spread this approach in Canada. The study objectives were to conduct an economic evaluation of “the Program” compared to the status quo. Methods A probabilistic decision analytic model was used to compare the expected costs, the quality-adjusted life years (QALYs) and the return on investment associated with the Program compared to the status quo from a publicly funded healthcare payer perspective. Effectiveness data and Program costs, expressed in 2022 Canadian dollars, from each jurisdiction were supplemented with literature data. Probabilistic sensitivity analyses varying key model assumptions were conducted. Results Analyses of 5416 9-1-1 calls from five jurisdictions where paramedics provided support to people with palliative care needs between April 1, 2020 and March 31, 2022 indicated that 60% of the 9-1-1 calls under the Program enabled people to avoid transport to the emergency department and receive palliative care at home. Treating people at home saved paramedics an average of 31 min (range from 15 to 67). The Program was associated with cost savings of $2773 (95% confidence interval [CI] $1539–$4352) and an additional 0.00069 QALYs (95% CI 0.00024–0.00137) per 9-1-1 palliative care call. The Program return on investment was $4.6 for every $1 invested. Threshold analyses indicated that in order to be cost saving, 33% of 9-1-1 calls should be treated at home under the Program, the Program should generate a minimum of 97 calls per year with each call costing no more than $2773. Conclusion The Program was cost-effective in the majority of the scenarios examined. These results support the implementation of paramedic-based palliative care at home programs in Canada.

As a hot topic in Landscape Ecology study,ecological connectivity is an important indicator for regional land sustainable use and biological protection. This paper conducted a systematic assessment of ecological connectivity using remote sensing images of Dongshan Island in 1994, 2003 and2011. Based on least-cost modelling, the method takes into consideration the type of barrier, the distance impact, and the adjacent land use types to obtain the Barrier Effect Index（BEI） and Ecological Connectivity Index（ECI）. The application of this method to Dongshan Island showed the ecological connectivity index（ECI） was low in 1994, improved in 2003, and decreased significantly in 2011. The results of the dynamic analysis of landscape structure showed farmland and roads were the main landscape classes that caused the low observed ECI in 1994 and 2003;these tended to divide the landscape and cause fragmentation. Construction land and roads were the main landscape classes resulting in low ECI in 2011,while forest and grassland had a high ECI. Trajectory analysis showed ECI tended to decrease in the low mountain forest zone of the northwestern and southeastern parts of Dongshan Island as well as in the coastal protection forest area. The areas where ECI became high were located in the northeastern part of Dongshan Island where cities and towns are concentrated with high human populations.Therefore, rapid urbanization has been the most important factor driving changes in landscape structure and patterns during the last 17 years on Dongshan Island. The approach not only assists us in revealing the driving mechanism of landscape dynamics from another aspect, but also can assess the impacts of regional and urban plans on landscape structure and function.

Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival. Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 [95% CI 0·437–0·994], one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 [75%] of 92 vs 14 [16%] of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred. Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen. Pfizer, Shinpoong, and Daewoong Korea and Takeda.

COSINE is a dark matter search experiment based on an array of low background NaI(Tl) crystals located at the Yangyang underground laboratory. The assembly of COSINE-100 was completed in the summer of 2016 and the detector is currently collecting physics quality data aimed at reproducing the DAMA/LIBRA experiment that reported an annual modulation signal. Stable operation has been achieved and will continue for at least 2 years. Here, we describe the design of COSINE-100, including the shielding arrangement, the configuration of the NaI(Tl) crystal detection elements, the veto systems, and the associated operational systems, and we show the current performance of the experiment.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo. A comprehensive analysis of antibody neutralization activity against a panel of authentic isolates and chimeric SARS-CoV-2 variants shows markedly diminished neutralizing activity against the variant B.1.351, first identified in South Africa.

There is increasing recognition that the two measures in the Heaviness of Smoking Index (HSI), time to first cigarette of the day (TTFC) and daily consumption (cigarettes per day [CPD]), are strong predictors of quitting behavior. Use of Waves 1-4 of International Tobacco Control cohort with around 8,000 respondents per wave and 6,000 for prediction of quit outcomes at the next wave. We measured TTFC and CPD at each wave and quit outcomes at the next wave. We also looked at the relative utility of the standard categorical scoring compared with a continuous score using the square root of CPD minus the natural log of TTFC in minutes. We found considerable consistency of the measures across years with a small decrease as duration between measurements increased. For a 3-year gap, the correlations were .72 and .70 for the continuous and categorical composite HSI measures, respectively, and were at least .63 for the individual components. Both TTFC and CPD independently predicted maintenance of quit attempts (for at least 1 month) in each of the three wave-to-wave replications, and these effects were maintained when controlling for demographic factors. CPD also predicted making attempts consistently, but the results for TTFC was not consistently significant. Both TTFC and CPD are fairly reliable over time and are important predictors of quitting. There are only small effects of mode of computing the scores, and the two items can be used either individually or combined as the HSI.

Chemical modifications of histones can mediate diverse DNA-templated processes, including gene transcription 1 – 3 . Here we provide evidence for a class of histone post-translational modification, serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in organisms that produce serotonin (also known as 5-hydroxytryptamine (5-HT)). We demonstrate that tissue transglutaminase 2 can serotonylate histone H3 tri-methylated lysine 4 (H3K4me3)-marked nucleosomes, resulting in the presence of combinatorial H3K4me3Q5ser in vivo. H3K4me3Q5ser displays a ubiquitous pattern of tissue expression in mammals, with enrichment observed in brain and gut, two organ systems responsible for the bulk of 5-HT production. Genome-wide analyses of human serotonergic neurons, developing mouse brain and cultured serotonergic cells indicate that H3K4me3Q5ser nucleosomes are enriched in euchromatin, are sensitive to cellular differentiation and correlate with permissive gene expression, phenomena that are linked to the potentiation of TFIID 4 – 6 interactions with H3K4me3. Cells that ectopically express a H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser-target loci, which leads to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signalling, in the mediation of permissive gene expression. In serotonin-rich tissues, tissue transglutaminase 2 is able to attach serotonin to a glutamine residue in histone H3; this modification mediates permissive gene expression in these tissues.

The COSINE-100 dark matter search experiment is an array of NaI(Tl) crystal detectors located in the Yangyang Underground Laboratory (Y2L). To understand measured backgrounds in the NaI(Tl) crystals we have performed Monte Carlo simulations using the Geant4 toolkit and developed background models for each crystal that consider contributions from both internal and external sources, including cosmogenic nuclides. The background models are based on comparisons of measurement data with Monte Carlo simulations that are guided by a campaign of material assays and are used to evaluate backgrounds and identify their sources. The average background level for the six crystals (70 kg total mass) that are studied is 3.5 counts/day/keV/kg in the (2–6) keV energy interval. The dominant contributors in this energy region are found to be 210Pb and 3H.