Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Cost- effectiveness of long- acting insulin analogues vs intermediate/long- acting human insulin for type 1 diabetes: A population- based cohort followed over 10 years

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154921/1/bcp14188.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154921/2/bcp14188_am.pd

Effect of metformin by employing 2-hour postload insulin for measuring insulin resistance in Taiwanese women with polycystic ovary syndrome

Evidence on clinical effectiveness of metformin in ethnic Chinese women with polycystic ovary syndrome (PCOS) remains scarce. Standard diagnostic approaches to identify insulin resistance (IR) cases in PCOS patients might be invasive, labor intensive, and stressful for patients (i.e., euglycemic clamp), or somewhat complicated for clinicians to calculate and monitor in routine practice [i.e., the homeostatic model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI)]. The aim of this study was to evaluate the clinical effects of metformin in Taiwanese women with PCOS and identify the feasible diagnostic measures of IR for Taiwanese women with PCOS. Methods: A total of 114 women from a medical center in Taiwan were studied. All were aged between 18 years and 45 years, diagnosed with PCOS according to the Rotterdam criteria, and treated with metformin. Outcome end points were body mass index (BMI) and 2-hour postload glucose and insulin levels from a 75-g oral glucose tolerance test. Results: BMI in overweight patients were significantly improved with metformin treatment duration (p < 0.001). The 2-hour insulin level statistically improved after treatment (before: 80.7 ± 63.9 μIU/mL vs. after: 65.0 ± 60.4 μIU/mL; p = 0.009). The improved 2-hour insulin level was significantly greater in IR patients than in non-IR patients. Compared with the 2-hour postload insulin level, the fasting insulin level provided 18.15% sensitivity and 94.12% specificity, the HOMA yielded 40% sensitivity and 70.58% specificity, and the QUICKI achieved 63.63% sensitivity and 11.76% specificity. Conclusion: Clinical outcomes in Taiwanese PCOS women were improved with metformin treatment, especially in overweight and IR patients. The 2-hour postload insulin level appears to be a convenient tool for screening IR in Taiwanese patients

Pharmacoeconomic analysis of antifungal therapy for primary treatment of invasive candidiasis caused by Candida albicans and non-albicans Candida species

Abstract Background Cost-effectiveness studies of echinocandins for the treatment of invasive candidiasis, including candidemia, are rare in Asia. No study has determined whether echinocandins are cost-effective for both Candida albicans and non-albicans Candida species. There have been no economic evaluations that compare non-echinocandins with the three available echinocandins. This study was aimed to assess the cost-effectiveness of individual echinocandins, namely caspofungin, micafungin, and anidulafungin, versus non-echinocandins for C. albicans and non-albicans Candida species, respectively. Methods A decision tree model was constructed to assess the cost-effectiveness of echinocandins and non-echinocandins for invasive candidiasis. The probability of treatment success, mortality rate, and adverse drug events were extracted from published clinical trials. The cost variables (i.e., drug acquisition) were based on Taiwan’s healthcare system from the perspective of a medical payer. One-way sensitivity analyses and probability sensitivity analyses were conducted. Results For treating invasive candidiasis (all species), as compared to fluconazole, micafungin and caspofungin are dominated (less effective, more expensive), whereas anidulafungin is cost-effective (more effective, more expensive), costing US$3666.09 for each life-year gained, which was below the implicit threshold of the incremental cost-effectiveness ratio in Taiwan. For C. albicans, echinocandins are cost-saving as compared to non-echinocandins. For non-albicans Candida species, echinocandins are cost-effective as compared to non-echinocandins, costing US$652 for each life-year gained. The results were robust over a wide range of sensitivity analyses and were most sensitive to the clinical efficacy of antifungal treatment. Conclusions Echinocandins, especially anidulafungin, appear to be cost-effective for invasive candidiasis caused by C. albicans and non-albicans Candida species in Taiwan

Cost‐effectiveness of long‐acting insulin analogues vs

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154921/1/bcp14188.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154921/2/bcp14188_am.pd

Cost-effectiveness of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors among patients with type 2 diabetes with and without established cardiovascular diseases: A model-based simulation analysis using 10-year real-world data and targeted literature review

AimWe conducted a model-based economic analysis of sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) in patients with type 2 diabetes (T2D), with and without established cardiovascular diseases (CVDs), using 10-year real-world data.Materials and MethodsA Markov model was utilized to estimate healthcare costs and quality-adjusted life-years (QALYs) over a 10-year simulation time horizon from a healthcare sector perspective, with both costs and QALYs discounted at 3% annually. Model inputs were derived from analyses of Taiwan’s National Health Insurance Research Database or published studies of Taiwanese populations. The primary outcome measure was the incremental cost-effectiveness ratios (ICERs). Incorporated with our study findings, a targeted literature review was conducted to synthesize updated evidence on the cost-effectiveness of SGLT2is versus DPP4is.ResultsOver 10 years, use of SGLT2is versus DPP4is yielded ICERs of $3244 and$4186 per QALY gained for patients with T2D, with and without established CVDs, respectively. Results were robust across a series of sensitivity and scenario analyses, showing ICERs between $-1074 (cost-saving) and$8467 per QALY gained for patients with T2D with established CVDs and between $369 and$37 122 per QALY gained for patients with T2D without established CVDs.ConclusionsUse of SGLT2is versus DPP4is was highly cost-effective for patients with T2D regardless of their CVD history in real-world clinical practice. Our results extend current evidence by showing SGLT2is as an economically rational alternative over DPP4is for T2D treatment in routine care. Future research is warranted to explore the heterogeneous economic benefits of SGLT2is given diverse patient characteristics in clinical settings.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172989/1/dom14708.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172989/2/dom14708_am.pd