Kheper, a Novel ZFH/δEF1 Family Member, Regulates the Development of the Neuroectoderm of Zebrafish (Danio rerio)

AbstractKheper is a novel member of the ZFH (zinc-finger and homeodomain protein)/δEF1 family in zebrafish. kheper transcripts are first detected in the epiblast of the dorsal blastoderm margin at the early gastrula stage and kheper is expressed in nearly all the neuroectoderm at later stages. kheper expression was expanded in noggin RNA-injected embryos and also in swirl mutant embryos and was reduced in bmp4 RNA-injected embryos and chordino mutant embryos, suggesting that kheper acts downstream of the neural inducers Noggin and Chordino. Overexpression of Kheper elicited ectopic expansion of the neuroectoderm-specific genes fkd3, hoxa-1, and eng3, and the ectopic expression of hoxa-1 was not inhibited by BMP4 overexpression. Kheper interacted with the transcriptional corepressors CtBP1 and CtBP2. Overexpression of a Kheper mutant lacking the homeodomain or of a VP16–Kheper fusion protein disturbed the development of the neuroectoderm and head structures. These data underscore the role of Kheper in the development of the neuroectoderm and indicate that Kheper acts as a transcriptional repressor

Shortened cataract surgery by standardisation of the perioperative protocol according to the Joint Commission International accreditation: a retrospective observational study

OBJECTIVES: To investigate the impact of standardisation of the perioperative protocol based on the Joint Commission International (JCI) accreditation guidelines for operating time in cataract surgery. DESIGN: Retrospective observational study. SETTING: Single centre in Japan. PARTICIPANTS: Between March 2014 and June 2016, 3127 patients underwent cataract surgery under topical anaesthesia including 2581 and 546 patients before and after JCI accreditation, respectively. PRIMARY AND SECONDARY OUTCOMES: We compared three time periods, comprising the preprocedure/surgery time (pre-PT), PT and post-PT, and total PT (TPT) of cataract surgery between patients before and after JCI accreditation, by regression analysis adjusted for age, sex and cataract surgery-associated confounders. RESULTS: The main outcomes were pre-PT, PT, post-PT and TPT. Pre-PT (19.8+/-10.5 vs 13.9+/-8.5 min, p \u3c 0.001) and post-PT (3.5+/-4.6 vs 2.6+/-2.1 min, p \u3c 0.001) significantly decreased after JCI accreditation, while PT did not significantly change (16.8+/-6.7 vs 16.2+/-6.3 min, p=0.065). Consequently, TPT decreased on average by 7.3 min per person after JCI accreditation (40.1+/-13.4 vs 32.8+/-10.9 min, p \u3c 0.001). After adjusting for confounders, pre-PT (beta=-5.82 min, 95% CI -6.75 to -4.88), PT (beta=-0.76 min, 95% CI -1.34 to -1.71), post-PT (beta=-0.85 min, 95% CI -1.24 to -0.45) and TPT (beta=-7.43 min, 95% CI -8.61 to -6.24) were significantly shortened after JCI accreditation. CONCLUSION: Perioperative protocol standardisation, based on JCI accreditation, shortened TPT in cataract surgery under local anaesthesia

IFMIF, the European–Japanese efforts under the Broader Approach agreement towards a Li(d,xn) neutron source: Current status and future options

The necessity of a neutron source for fusion materials research was identified already in the 70s. Though neutrons induced degradation present similarities on a mechanistic approach, thresholds energies for crucial transmutations are typically above fission neutrons spectrum. The generation of He via 56Fe (n,α) 53Cr in future fusion reactors with around 12 appm/dpa will lead to swelling and structural materials embrittlement. Existing neutron sources, namely fission reactors or spallation sources lead to different degradation, attempts for extrapolation are unsuccessful given the absence of experimental observations in the operational ranges of a fusion reactor. Neutrons with a broad peak at 14 MeV can be generated with Li(d,xn) reactions; the technological efforts that started with FMIT in the early 80s have finally matured with the success of IFMIF/EVEDA under the Broader Approach Agreement. The status today of five technological challenges, perceived in the past as most critical, are addressed. These are: 1. the feasibility of IFMIF accelerators, 2. the long term stability of lithium flow at IFMIF nominal conditions, 3. the potential instabilities in the lithium screen induced by the 2 × 5 MW impacting deuteron beam, 4. the uniformity of temperature in the specimens during irradiation, and 5. the validity of data provided with small specimens. Other ideas for fusion material testing have been considered, but they possibly are either not technologically feasible if fixed targets are considered or would require the results of a Li(d,xn) facility to be reliably designed. In addition, today we know beyond reasonable doubt that the cost of IFMIF, consistently estimated throughout decades, is marginal compared with the cost of a fusion reactor. The less ambitious DEMO reactor performance being considered correlates with a lower need of fusion neutrons flux; thus IFMIF with its two accelerators is possibly not needed since with only one accelerator as the European DONES or the Japanese A-FNS propose, the present needs > 10 dpa/fpy would be fulfilled. World fusion roadmaps stipulate a fusion relevant neutron source by the middle of next decade, the success of IFMIF/EVEDA phase is materializing this four decades old dream

Comparison among random forest, logistic regression, and existing clinical risk scores for predicting outcomes in patients with atrial fibrillation: A report from the J-RHYTHM registry

BACKGROUND: Machine learning (ML) has emerged as a promising tool for risk stratification. However, few studies have applied ML to risk assessment of patients with atrial fibrillation (AF). HYPOTHESIS: We aimed to compare the performance of random forest (RF), logistic regression (LR), and conventional risk schemes in predicting the outcomes of AF. METHODS: We analyzed data from 7406 nonvalvular AF patients (median age 71 years, female 29.2%) enrolled in a nationwide AF registry (J‐RHYTHM Registry) and who were followed for 2 years. The endpoints were thromboembolisms, major bleeding, and all‐cause mortality. Models were generated from potential predictors using an RF model, stepwise LR model, and the thromboembolism (CHADS(2) and CHA(2)DS(2)‐VASc) and major bleeding (HAS‐BLED, ORBIT, and ATRIA) scores. RESULTS: For thromboembolisms, the C‐statistic of the RF model was significantly higher than that of the LR model (0.66 vs. 0.59, p = .03) or CHA(2)DS(2)‐VASc score (0.61, p < .01). For major bleeding, the C‐statistic of RF was comparable to the LR (0.69 vs. 0.66, p = .07) and outperformed the HAS‐BLED (0.61, p < .01) and ATRIA (0.62, p < .01) but not the ORBIT (0.67, p = .07). The C‐statistic of RF for all‐cause mortality was comparable to the LR (0.78 vs. 0.79, p = .21). The calibration plot for the RF model was more aligned with the observed events for major bleeding and all‐cause mortality. CONCLUSIONS: The RF model performed as well as or better than the LR model or existing clinical risk scores for predicting clinical outcomes of AF

Radiological prediction of tumor invasiveness of lung adenocarcinoma on thin-section CT

To evaluate thin-section computed tomography (CT) (TSCT) features that differentiate adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IVA), and to determine the size of solid portion on CT that correlates to pathological invasive components. Forty-eight patients were included. Nodules were classified into ground-glass nodule (GGN), part-solid, solid, and heterogeneous. Visual density of GGNs was subjectively evaluated using reference standard images: faint GGN (Ga), −400 HU; and mixed (Ga + Gb, Ga + Gc, and Gb + Gc). The evaluated TSCT findings included margin of nodule, distribution of solid portion, distribution of air bronchiologram, and pleural indentation. The longest diameters of the solid portion and the entire tumor were measured. Invasive diameters were measured in pathological specimens. Twenty-two AISs (16 GGNs [7 Ga, 5 Gb, 2 Gc, 1 Ga + Gc, 1 Gb + Gc], 4 part-solids, and 2 heterogeneous), 6 MIAs (1 GGN [Gb + Gc], 3 part-solids, and 2 solids), and 20 IVAs (1 GGN [Gb], 3 part-solids, and 16 solid) were found. The longest diameter (mean ± standard deviation) of the solid portion and total tumor were 9.7 ± 9.7 and 18.9 ± 5.6 mm, respectively. Significant differences in TSCT findings between AIS and IVA were margin of nodule (Pearson chi-squared test, P = 0.004), distribution of air bronchiologram (P = 0.0148), and pleural indentation (P = 0.0067). A solid portion >5.3 mm on TSCT indicated MIA or IVA, and >7.3 mm indicated IVA (receiver operating characteristic analysis, P 7.3 mm on TSCT indicates IVA

Inappropriate implantable cardioverter defibrillator shocks—incidence, effect, and implications for driver licensing

PurposePatients with implantable cardioverter defibrillators (ICDs) have an ongoing risk of sudden incapacitation that may cause traffic accidents. However, there are limited data on the magnitude of this risk after inappropriate ICD therapies. We studied the rate of syncope associated with inappropriate ICD therapies to provide a scientific basis for formulating driving restrictions.MethodsInappropriate ICD therapy event data between 1997 and 2014 from 50 Japanese institutions were analyzed retrospectively. The annual risk of harm (RH) to others posed by a driver with an ICD was calculated for private driving habits. We used a commonly employed annual RH to others of 5 in 100,000 (0.005%) as an acceptable risk threshold.ResultsOf the 4089 patients, 772 inappropriate ICD therapies occurred in 417 patients (age 61 ± 15 years, 74% male, and 65% secondary prevention). Patients experiencing inappropriate therapies had a mean number of 1.8 ± 1.5 therapy episodes during a median follow-up period of 3.9 years. No significant differences were found in the age, sex, or number of inappropriate therapies between patients receiving ICDs for primary or secondary prevention. Only three patients (0.7%) experienced syncope associated with inappropriate therapies. The maximum annual RH to others after the first therapy in primary and secondary prevention patients was calculated to be 0.11 in 100,000 and 0.12 in 100,000, respectively.ConclusionsWe found that the annual RH from driving was far below the commonly cited acceptable risk threshold. Our data provide useful information to supplement current recommendations on driving restrictions in ICD patients with private driving habits

Very Early Diuretic Response After Admission for Acute Heart Failure

BACKGROUND: In hospitalized heart failure patients, a poor diuretic response (DR) during the first days of hospital admission is associated with worse outcomes. However, it remains unknown whether diuretic response in the first hours has similar prognostic value. Moreover, data on the sequential change in DR during hospital admission are lacking. METHODS AND RESULTS: DR (urine output per 40 mg furosemide-equivalent diuretics dose) was measured from 0 to 6 hours (DR6), 6 to 48 hours (DR6-48), and 0 to 48 hours (DR48) of the patient's arrival to the emergency department (ED) in 1551 patients with AHF (mean age 78 years old; 56% were male; and 48% were de-novo patients with heart failure). Patients with a poor DR within the first 6 hours were older age, had worse renal function and were already on diuretic treatment before admission. DR6 was only weakly correlated with DR6-48 (Spearman's rho=0.273; p<0.001). DR6, DR6-48 and DR48 were all significantly associated with 60-day mortality independent of other prognostic factors. DR6 and DR48 showed comparable prognostic ability. However, the model combining DR6 with DR6-48 significantly exceeded both DR6 (NRI: 0.249, p=0.032) and DR48 (NRI: 0.287, p=0.025) with regard to 60-day mortality prediction. CONCLUSION: Both DR measured within the first 6 hours of ED arrival and DR measured during the first 48 hours in patients with AHF have similar prognostic value, although they were moderately correlated. Changes in DR over time provide additional prognostic information

Impact of early treatment with intravenous vasodilators and blood pressure reduction in acute heart failure

Objective Although vasodilators are used in acute heart failure (AHF) management, there have been no clear supportive evidence regarding their routine use. Recent European guidelines recommend systolic blood pressure (SBP) reduction in the range of 25% during the first few hours after diagnosis. This study aimed to examine clinical and prognostic significance of early treatment with intravenous vasodilators in relation to their subsequent SBP reduction in hospitalised AHF. Methods We performed post hoc analysis of 1670 consecutive patients enrolled in the Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure. Intravenous vasodilator use within 6 hours of hospital arrival and subsequent SBP changes were analysed. Outcomes were gauged by 1-year mortality and diuretic response (DR), defined as total urine output 6 hours posthospital arrival per 40 mg furosemide-equivalent diuretic use. Results Over half of the patients (56.0%) were treated with intravenous vasodilators within the first 6 hours. In this vasodilator-treated cohort, 554 (59.3%) experienced SBP reduction 25%. In patients experiencing Conclusions Intravenous vasodilator therapy was associated with greater DR and lower mortality, provided SBP reduction was less than 25%. Our results highlight the importance in early administration of intravenous vasodilators without causing excess SBP reduction in AHF management

Involvement of SIK3 in Glucose and Lipid Homeostasis in Mice

Salt-inducible kinase 3 (SIK3), an AMP-activated protein kinase-related kinase, is induced in the murine liver after the consumption of a diet rich in fat, sucrose, and cholesterol. To examine whether SIK3 can modulate glucose and lipid metabolism in the liver, we analyzed phenotypes of SIK3-deficent mice. Sik3−/− mice have a malnourished the phenotype (i.e., lipodystrophy, hypolipidemia, hypoglycemia, and hyper-insulin sensitivity) accompanied by cholestasis and cholelithiasis. The hypoglycemic and hyper-insulin-sensitive phenotypes may be due to reduced energy storage, which is represented by the low expression levels of mRNA for components of the fatty acid synthesis pathways in the liver. The biliary disorders in Sik3−/− mice are associated with the dysregulation of gene expression programs that respond to nutritional stresses and are probably regulated by nuclear receptors. Retinoic acid plays a role in cholesterol and bile acid homeostasis, wheras ALDH1a which produces retinoic acid, is expressed at low levels in Sik3−/− mice. Lipid metabolism disorders in Sik3−/− mice are ameliorated by the treatment with 9-cis-retinoic acid. In conclusion, SIK3 is a novel energy regulator that modulates cholesterol and bile acid metabolism by coupling with retinoid metabolism, and may alter the size of energy storage in mice