Perturbation of Retinoid Homeostasis Increases Malformation Risk in Embryos Exposed to Pregestational Diabetes

Pregestational diabetes is highly associated with increased risk of birth defects. However, factors that can increase or reduce expressivity and penetrance of malformations in diabetic pregnancies remain poorly identified. All-trans retinoic acid (RA) plays crucial roles in embryogenesis. Here, we find that Cyp26a1, which encodes a key enzyme for catabolic inactivation of RA required for tight control of local RA concentrations, is significantly down-regulated in embryos of diabetic mice. Embryonic tissues expressing Cyp26a1 show reduced efficiency of RA clearance. Diabetes-exposed embryos are thus sensitized to RA and more vulnerable to the deleterious effects of increased RA signalling. Susceptibility to RA teratogenesis is further potentiated in embryos with a pre-existing genetic defect of RA metabolism. Increasing RA clearance efficiency by a pre-conditioning approach can counteract the increased susceptibility to RA teratogenesis in embryos of diabetic mice. Our findings provide new insight into gene-environment interactions that influence individual risk in manifestation of diabetes-related birth defects, and shed light on the environmental risk factors and genetic variants for a stratified medicine approach to screen diabetic women of childbearing age and assess risk of birth defects during pregnancy

Trends of sex differences in outcomes of cardiac electronic device implantations in the United States

Background The disparity in outcomes of CIED implantations between sexes has been previously demonstrated in device-specific cohorts (e.g. implantable cardioverter defibrillators (ICD)). However, it is unclear whether sex differences are present with all types of CIED and, if so, what the trends of such differences were in recent years. Methods Using the National Inpatient Sample, all hospitalizations between 2004 and 2014 for de novo implantation of permanent pacemakers (PPM), cardiac resynchronization therapy with or without a defibrillator (CRT-D and CRT-P, respectively) and ICD were analyzed to examine the association between sex and in-hospital acute complications of CIED implantation. Results Out of 2,815,613 hospitalizations for de novo CIED implantation, 41.9% were performed on women. Women were associated with increased adjusted odds of adverse procedural complications (major adverse cardiovascular complications: 1.17 [1.16, 1.19], bleeding: 1.13 [1.12, 1.15], thoracic: 1.42 [1.40, 1.44], cardiac: 1.44 [1.38, 1.50]), while the adjusted odds of in-hospital all-cause mortality compared to men was 0.96 [0.94, 1.00]. The odds of adverse complications in the overall CIED cohort were persistently raised in women throughout the study period, whereas similar odds of all-cause mortality across the sexes were observed throughout the study period. Conclusion In a national cohort of CIED implantations we demonstrate that women are at an overall higher risk of procedure-related adverse events compared to men, but no increased risk of all-cause mortality. Further studies are required to identify procedural techniques that would improve outcomes amongst women undergoing such procedures

Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine

Background: Intranasal dexmedetomidine produces safe, effective sedation in children and adults. It may be administered by drops from a syringe or by nasal mucosal atomization (MAD NasalTM). / Methods: This prospective, three-period, crossover, double-blind study compared the pharmacokinetic (PK) and pharmacodynamic (PD) profile of i.v. administration with these two different modes of administration. In each session each subject received 1 μg kg−1 dexmedetomidine, either i.v., intranasal with the atomizer or intranasal by drops. Dexmedetomidine plasma concentration and Ramsay sedation score were used for PK/PD modelling by NONMEM. / Results: The i.v. route had a significantly faster onset (15 min, 95% CI 15–20 min) compared to intranasal routes by atomizer (47.5 min, 95% CI 25–135 min), and by drops (60 min, 95%CI 30–75 min), (P<0.001). There was no significant difference in sedation duration across the three treatment groups (P=0.88) nor in the median onset time between the two modes of intranasal administration (P=0.94). A 2-compartment disposition model, with transit intranasal absorption and clearance driven by cardiac output using the well-stirred liver model, was the final PK model. Intranasal bioavailability was estimated to be 40.6% (95% CI 34.7–54.4%) and 40.7% (95% CI 36.5–53.2%) for atomization and drops respectively. Sedation score was modelled via a sigmoidal Emax model driven by an effect compartment. The effect compartment had an equilibration half time 3.3 (95% CI 1.8–4.7) min−1, and the EC50 was estimated to be 903 (95% CI 450–2344) pg ml−1. / Conclusions: There is no difference in bioavailability with atomization or nasal drops. A similar degree of sedation can be achieved by either method. / Clinical trial registration: HKUCTR-1617

Readmission and processes of care across weekend and weekday hospitalisation for acute myocardial infarction, heart failure or stroke: an observational study of the National Readmission Database.

OBJECTIVES: Variation in hospital resource allocations across weekdays and weekends have led to studies of the 'weekend effect' for ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), heart failure (HF) and stroke. However, few studies have explored the 'weekend effect' on unplanned readmission. We aimed to investigate 30-day unplanned readmissions and processes of care across weekend and weekday hospitalisations for STEMI, NSTEMI, HF and stroke. DESIGN: We grouped hospitalisations for STEMI, NSTEMI, HF or stroke into weekday or weekend admissions. Multivariable adjusted ORs for binary outcomes across weekend versus weekday (reference) groups were estimated using logistic regression. SETTING: We included all non-elective hospitalisations for STEMI, NSTEMI, HF or stroke, which were recorded in the US Nationwide Readmissions Database between 2010 and 2014. PARTICIPANTS: The analysis sample included 659 906 hospitalisations for STEMI, 1 420 600 hospitalisations for NSTEMI, 3 027 699 hospitalisations for HF, and 2 574 168 hospitalisations for stroke. MAIN OUTCOME MEASURES: The primary outcome was unplanned 30-day readmission. As secondary outcomes, we considered length of stay and the following processes of care: coronary angiography, primary percutaneous coronary intervention, coronary artery bypass graft, thrombolysis, brain scan/imaging, thrombectomy, echocardiography and cardiac resynchronisation therapy/implantable cardioverter-defibrillator. RESULTS: Unplanned 30-day readmission rates were 11.0%, 15.1%, 23.0% and 10.9% for STEMI, NSTEMI, HF and stroke, respectively. Weekend hospitalisations for HF were associated with a statistically significant but modest increase in 30-day readmissions (OR of 1.045, 95% CI 1.033 to 1.058). Weekend hospitalisation for STEMI, NSTEMI or stroke was not associated with increased risk of 30-day readmission. CONCLUSION: There was no clinically meaningful evidence against the supposition that weekend and weekday hospitalisations have the same 30-day unplanned readmissions. Thirty-day readmission rates were high, especially for HF, which has implications for service provision. Strategies to reduce readmission rates should be explored, regardless of day of hospitalisation

Biomaterials Approaches to Combating Oral Biofilms and Dental Disease

Background: Possibilities for biomaterials to impact the dental caries epidemic are reviewed with emphasis placed on novel delivery biomaterials and new therapeutic targets

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Imaging of acute appendicitis in children: EU versus US ... or US versus CT? A European perspective

There is substantial evidence that imaging may reduce the negative appendectomy rate, also in children. However, controversy exists about the preferred method: US or CT, and the choice appears to be determined by the side of the Atlantic Ocean. This review brings forth several arguments in favour of U

Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations

Abstract Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidence-based guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline