The retrospective forecast skill of three coupled climate models (NCEP CFS, GFDL CM2.1, and CAWCR POAMA 1.5) and their multi-model ensemble (MME) is evaluated, focusing on the Northern Hemisphere ...(NH) summer upper-tropospheric circulation along with surface temperature and precipitation for the 25-year period of 1981–2005. The seasonal prediction skill for the NH 200-hPa geopotential height basically comes from the coupled models’ ability in predicting the first two empirical orthogonal function (EOF) modes of interannual variability, because the models cannot replicate the residual higher modes. The first two leading EOF modes of the summer 200-hPa circulation account for about 84% (35.4%) of the total variability over the NH tropics (extratropics) and offer a hint of realizable potential predictability. The MME is able to predict both spatial and temporal characteristics of the first EOF mode (EOF1) even at a 5-month lead (January initial condition) with a pattern correlation coefficient (PCC) skill of 0.96 and a temporal correlation coefficient (TCC) skill of 0.62. This long-lead predictability of the EOF1 comes mainly from the prolonged impacts of El Niño-Southern Oscillation (ENSO) as the EOF1 tends to occur during the summer after the mature phase of ENSO. The second EOF mode (EOF2), on the other hand, is related to the developing ENSO and also the interdecadal variability of the sea surface temperature over the North Pacific and North Atlantic Ocean. The MME also captures the EOF2 at a 5-month lead with a PCC skill of 0.87 and a TCC skill of 0.67, but these skills are mainly obtained from the zonally symmetric component of the EOF2, not the prominent wavelike structure, the so-called circumglobal teleconnection (CGT) pattern. In both observation and the 1-month lead MME prediction, the first two leading modes are accompanied by significant rainfall and surface air temperature anomalies in the continental regions of the NH extratropics. The MME’s success in predicting the EOF1 (EOF2) is likely to lead to a better prediction of JJA precipitation anomalies over East Asia and the North Pacific (central and southern Europe and western North America).
The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, ...identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.
Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. ...Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.
IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0–1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1–21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1–21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs ≥18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.
Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7·3 months (IQR 3·7–13·6). Median overall survival was 8·87 months (95% CI 7·00–10·61) with atezolizumab plus cobimetinib, 7·10 months (6·05–10·05) with atezolizumab, and 8·51 months (6·41–10·71) with regorafenib; the hazard ratio was 1·00 (95% CI 0·73–1·38; p=0·99) for the combination versus regorafenib and 1·19 (0·83–1·71; p=0·34) for atezolizumab versus regorafenib. Grade 3–4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3–4 adverse events in the combination group were diarrhoea (20 11% of 179), anaemia (ten 6%), increased blood creatine phosphokinase (12 7%), and fatigue (eight 4%). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).
IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.
F Hoffmann-La Roche Ltd/Genentech Inc.
A novel memory cell structure with a Pt/Ti‐doped NiO/Pt architecture is shown to exhibit the lowest write current reported thus far for a unipolar switching resistance‐change‐based device, as shown ...in the figure. The write current decreases dramatically upon scaling to cell sizes smaller than 100 nm×100 nm. High‐density universal memory can be fabricated by combining this node element with a selective switch.
Summary
Despite ethnic differences in cortisol sensitivity, only one study in Caucasians has assessed trabecular bone score (TBS) in patients with subclinical hypercortisolism (SH). We showed that ...both subtle cortisol excess and reduced adrenal androgen may contribute to impaired bone quality in Asian women with SH.
Introduction
One study in Caucasians has assessed trabecular bone score (TBS), an index of bone microstructure, in adrenal incidentaloma (AI) patients with subclinical hypercortisolism (SH). There are ethnic differences in cortisol sensitivities between Caucasian and Asian populations. We investigated the associations of cortisol and the adrenal androgen dehydroepiandrosterone-sulfate (DHEA-S) with TBS in AI patients with SH, adrenal Cushing’s syndrome (CS), and nonfunctional AI (NFAI).
Methods
We measured TBS, cortisol levels after the overnight 1 mg dexamethasone suppression test (1 mg DST), and cortisol/DHEA-S in 61 patients with SH (30 men; 31 women), 19 with adrenal CS (4 men; 15 women), and 355 with NFAI (213 men; 142 women).
Results
After adjusting for confounders, the serum cortisol level after 1 mg DST was inversely correlated with TBS in men (
β
= −0.133,
P
= 0.045) and women (
β
= − 0.140,
P
= 0.048). Higher cortisol/DHEA-S ratio was associated with lower TBS in women (
β
= − 0.252,
P
< 0.001), but not men. This inverse association of cortisol/DHEA-S ratio in women remained statistically significant after adjusting for the serum cortisol level after 1 mg DST (
β
= − 0.221,
P
= 0.008). Compared with women with NFAI, women with SH had 2.2% lower TBS (
P
= 0.040). Deteriorated bone microstructure (TBS < 1.230) was associated with the serum cortisol level after 1 mg DST (odds ratio OR, 2.18; 95% confidence interval CI, 1.04–4.53) and cortisol/DHEA-S ratio (OR, 2.05; 95% CI, 1.03–4.08).
Conclusions
Subtle cortisol excess in both genders and reduced DHEA-S, especially in women, may contribute to impaired bone quality in Asian patients with SH.
This paper presents the development of a disposable plastic biochip incorporating smart passive microfluidics with embedded on-chip power sources and integrated biosensor array for applications in ...clinical diagnostics and point-of-care testing. The fully integrated disposable biochip is capable of precise volume control with smart microfluidic manipulation without costly on-chip microfluidic components. The biochip has a unique power source using on-chip pressurized air reservoirs, for microfluidic manipulation, avoiding the need for complex microfluidic pumps. In addition, the disposable plastic biochip has successfully been tested for the measurements of partial oxygen concentration, glucose, and lactate level in human blood using an integrated biosensor array. This paper presents details of the smart passive microfluidic system, the on-chip power source, and the biosensor array together with a detailed discussion of the plastic micromachining techniques used for chip fabrication. A handheld analyzer capable of multiparameter detection of clinically relevant parameters has also been developed to detect the signals from the cartridge type disposable biochip. The handheld analyzer developed in this work is currently the smallest analyzer capable of multiparameter detection for point-of-care testing.
Summary
Analyses using the largest Korean cohort of adrenal incidentaloma (AI) revealed that subtle cortisol excess in premenopausal women and reduced dehydroepiandrosterone-sulfate (DHEA-S) in ...postmenopausal women and men are associated with bone mineral density (BMD) reduction in Asian patients with subclinical hypercortisolism (SH).
Introduction
Few studies evaluated bone metabolism in Asians with SH. We investigated associations of cortisol and DHEA-S, an adrenal androgen, with BMD in Asians with AI, with or without SH.
Methods
We used cross-sectional data of a prospective multicenter study from Korea. We measured BMD, bone turnover markers, cortisol levels after 1-mg dexamethasone suppression test (1-mg DST), DHEA-S, and baseline cortisol to DHEA-S ratio (cort/DHEA-S) in 109 AI patients with SH (18 premenopausal, 38 postmenopausal women, and 53 men) and 686 with non-functional AI (NFAI; 59 premenopausal, 199 postmenopausal women, and 428 men).
Results
Pre- and postmenopausal women, but not men, with SH had lower BMDs at lumbar spine (LS) than those with NFAI (
P
= 0.008~0.016). Premenopausal women with SH also had lower BMDs at the hip than those with NFAI (
P
= 0.009~0.012). After adjusting for confounders, cortisol levels after 1-mg DST demonstrated inverse associations with BMDs at all skeletal sites only in premenopausal women (
β
= − 0.042~− 0.033,
P
= 0.019~0.040). DHEA-S had positive associations with LS BMD in postmenopausal women (
β
= 0.096,
P
= 0.001) and men (
β
= 0.029,
P
= 0.038). The cort/DHEA-S had inverse associations with LS BMD in postmenopausal women (
β
= − 0.081,
P
= 0.004) and men (
β
= − 0.029,
P
= 0.011). These inverse associations of cort/DHEA-S remained significant after adjusting for cortisol levels after 1-mg DST (
β
= − 0.079~− 0.026,
P
= 0.006~0.029). In postmenopausal women, the odds ratios of lower BMD by DHEA-S and cort/DHEA-S was 0.26 (95% CI, 0.08–0.82) and 3.40 (95% CI, 1.12–10.33), respectively.
Conclusion
Subtle cortisol excess in premenopausal women and reduced DHEA-S in postmenopausal women and men may contribute to BMD reduction in Asians with SH.
Alumina supported bimetallic PdCu catalysts were prepared by simple incipient wetness impregnation followed by the process of atmospheric-pressure cold plasma reduction using Pd(NO
3
)
2
and Cu(NO
3
...)
2
as Pd and Cu precursors, respectively. The influence of reduction sequence and Pd/Cu atomic ratios on the structure and performance of the catalysts were investigated. The highest CO oxidation activity was obtained for the PdCu catalyst (PdCu/Al
2
O
3
–P) prepared by co-impregnation and reduction of the Pd and Cu precursors with a Pd/Cu atomic ratio of 1:1. Meantime, the PdCu/Al
2
O
3
–P catalyst prepared by cold plasma exhibits much higher performance than that prepared by conventional thermal reduction. The optimum results from the alloying degree, crystallite size and dispersion of PdCu nanoparticles, and the chemisorbed oxygen species on the surface of the support. As a result of the interaction between Pd and Cu species, high alloying degree, small size and high dispersion of PdCu nanoparticles in PdCu/Al
2
O
3
–P were obtained. In addition, due to the fast (6 min reduction) and low temperature reduction process, more active chemisorbed oxygen species were formed on the surface of PdCu/Al
2
O
3
–P. The results of diffuse reflectance fourier transform infrared and catalytic stability show that the interaction between Pd and carbon species is weakened, which may facilitate the adsorption and activation of O
2
. These make PdCu/Al
2
O
3
–P an excellent catalyst for CO oxidation. Atmospheric-pressure cold plasma is proved to be a facile and efficient method for fabricating high performance bimetallic PdCu catalysts, which may have potential applications for preparing other bimetallic catalysts.
Summary
In this large longitudinal study of 16,078 Korean men aged 50 years or older, we observed that baseline elevation of serum uric acid level significantly associated with a lower risk of ...incident fractures at osteoporosis-related sites during an average follow-up period of 3 years.
Introduction
Male osteoporosis and related fractures are becoming recognized as important public health concerns. Oxidative stress has detrimental effects on bone metabolism, and serum uric acid (UA) is known to be a strong endogenous antioxidant. In the present study, we performed a large longitudinal study with an average follow-up period of 3 years to clarify the role of UA on the risk of incident osteoporotic fractures (OFs).
Methods
A total of 16,078 Korean men aged 50 years or older who had undergone comprehensive routine health examinations were enrolled. Incident fractures at osteoporosis-related sites (e.g., hip, spine, distal radius, and proximal humerus) that occurred after the baseline examinations were identified from the nationwide claims database of the Health Insurance Review and Assessment Service of Korea by using selected International Classification of Diseases, 10th revision codes.
Results
In total, 158 (1.0 %) men developed incident OFs. The event rate was 33.1 per 10,000 person-years. Subjects without incident OFs had 6.0 % higher serum UA levels than subjects with OFs (
P
= 0.001). Multivariable-adjusted Cox proportional hazard analyses adjusted for age, body mass index, glomerular filtration rate, lifestyle factors, medical and drug histories, and the presence of baseline radiological vertebral fractures revealed that the hazard ratio per standard deviation increase of baseline UA levels for the development of incident OFs was 0.829 (95 % CI = 0.695–0.989,
P
= 0.038).
Conclusions
These data provide the epidemiological evidence that serum UA may act as a protective factor against the development of incident OFs in Korean men.
Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex ...differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59; p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females (OR = 1.19, p = 0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.
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