Cholesterol reduction from statin therapy has been one of the greatest public health successes in modern medicine. Simvastatin is among the most commonly used prescription medications. A ...non‐synonymous coding single‐nucleotide polymorphism (SNP), rs4149056, in SLCO1B1 markedly increases systemic exposure to simvastatin and the risk of muscle toxicity. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A) and clinical outcome for all statins. The strength of the evidence is high for myopathy with simvastatin. We limit our recommendations accordingly.
Clinical Pharmacology & Therapeutics (2012); 92 1, 112–117. doi:10.1038/clpt.2012.57
Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single‐nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to ...simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin‐induced myopathy.
Clinical Pharmacology & Therapeutics (2014); 96 4, 423–428. doi:10.1038/clpt.2014.125
Taylor A, Wang D, Patel K, Whittall R, Wood G, Farrer M, Neely RDG, Fairgrieve S, Nair D, Barbir M, Jones JL, Egan S, Everdale R, Lolin Y, Hughes E, Cooper JA, Hadfield SG, Norbury G, Humphries SE. ...Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project.
Cascade testing using DNA‐mutation information is now recommended in the UK for patients with familial hypercholesterolaemia (FH). We compared the detection rate and mutation spectrum in FH patients with a clinical diagnosis of definite (DFH) and possible (PFH) FH. Six hundred and thirty‐five probands from six UK centres were tested for 18 low‐density lipoprotein receptor gene (LDLR) mutations, APOB p.Arg3527Gln and PCSK9 p.Asp374Tyr using a commercial amplification refractory mutation system (ARMS) kit. Samples with no mutation detected were screened in all exons by single strand conformation polymorphism analysis (SSCP)/denaturing high performance liquid chromatography electrophoresis (dHPLC)/direct‐sequencing, followed by multiplex ligation‐dependent probe amplification (MLPA) to detect deletions and duplications in LDLR.The detection rate was significantly higher in the 190 DFH patients compared to the 394 PFH patients (56.3% and 28.4%, p > 0.00001). Fifty‐one patients had inadequate information to determine PFH/DFH status, and in this group the detection rate was similar to the PFH group (25.5%, p = 0.63 vs PFH). Overall, 232 patients had detected mutations (107 different; 6.9% not previously reported). The ARMS kit detected 100 (44%) and the MLPA kit 11 (4.7%). Twenty‐eight (12%) of the patients had the APOB p.Arg3527Gln and four (1.7%) had the PCSK9 p.Asp374Tyr mutation. Of the 296 relatives tested from 100 families, a mutation was identified in 56.1%. In 31 patients of Indian/Asian origin 10 mutations (two previously unreported) were identified. The utility of the ARMS kit was confirmed, but sequencing is still required in a comprehensive diagnostic service for FH. Even in subjects with a low clinical suspicion of FH, and in those of Indian origin, mutation testing has an acceptable detection rate.
Microbial metabolites, such as short-chain fatty acids (SCFAs), are highly produced in the intestine and potentially regulate the immune system. We studied the function of SCFAs in the regulation of ...T-cell differentiation into effector and regulatory T cells. We report that SCFAs can directly promote T-cell differentiation into T cells producing interleukin-17 (IL-17), interferon-γ, and/or IL-10 depending on cytokine milieu. This effect of SCFAs on T cells is independent of GPR41 or GPR43, but dependent on direct histone deacetylase (HDAC) inhibitor activity. Inhibition of HDACs in T cells by SCFAs increased the acetylation of p70 S6 kinase and phosphorylation rS6, regulating the mTOR pathway required for generation of Th17 (T helper type 17), Th1, and IL-10(+) T cells. Acetate (C2) administration enhanced the induction of Th1 and Th17 cells during Citrobacter rodentium infection, but decreased anti-CD3-induced inflammation in an IL-10-dependent manner. Our results indicate that SCFAs promote T-cell differentiation into both effector and regulatory T cells to promote either immunity or immune tolerance depending on immunological milieu.
Abstract
Nuclear charge radii are sensitive probes of different aspects of the nucleon–nucleon interaction and the bulk properties of nuclear matter, providing a stringent test and challenge for ...nuclear theory. Experimental evidence suggested a new magic neutron number at
N
= 32 (refs.
1–3
) in the calcium region, whereas the unexpectedly large increases in the charge radii
4,5
open new questions about the evolution of nuclear size in neutron-rich systems. By combining the collinear resonance ionization spectroscopy method with β-decay detection, we were able to extend charge radii measurements of potassium isotopes beyond
N
= 32. Here we provide a charge radius measurement of
52
K. It does not show a signature of magic behaviour at
N
= 32 in potassium. The results are interpreted with two state-of-the-art nuclear theories. The coupled cluster theory reproduces the odd–even variations in charge radii but not the notable increase beyond
N
= 28. This rise is well captured by Fayans nuclear density functional theory, which, however, overestimates the odd–even staggering effect in charge radii. These findings highlight our limited understanding of the nuclear size of neutron-rich systems, and expose problems that are present in some of the best current models of nuclear theory.
Molecular spectroscopy offers opportunities for the exploration of the fundamental laws of nature and the search for new particle physics beyond the standard model
. Radioactive molecules-in which ...one or more of the atoms possesses a radioactive nucleus-can contain heavy and deformed nuclei, offering high sensitivity for investigating parity- and time-reversal-violation effects
. Radium monofluoride, RaF, is of particular interest because it is predicted to have an electronic structure appropriate for laser cooling
, thus paving the way for its use in high-precision spectroscopic studies. Furthermore, the effects of symmetry-violating nuclear moments are strongly enhanced
in molecules containing octupole-deformed radium isotopes
. However, the study of RaF has been impeded by the lack of stable isotopes of radium. Here we present an experimental approach to studying short-lived radioactive molecules, which allows us to measure molecules with lifetimes of just tens of milliseconds. Energetically low-lying electronic states were measured for different isotopically pure RaF molecules using collinear resonance ionisation at the ISOLDE ion-beam facility at CERN. Our results provide evidence of the existence of a suitable laser-cooling scheme for these molecules and represent a key step towards high-precision studies in these systems. Our findings will enable further studies of short-lived radioactive molecules for fundamental physics research.
The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating monogenetic lysosomal disorders that affect children and young adults with no cure or effective treatment currently available. One ...of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutations in the palmitoyl-protein thioesterase 1 (PPT1) gene and severely reduces the child's lifespan to approximately 9 years of age. In order to better translate the human condition than is possible in mice, we sought to produce a large animal model employing CRISPR/Cas9 gene editing technology. Three PPT1 homozygote sheep were generated by insertion of a disease-causing PPT1 (R151X) human mutation into the orthologous sheep locus. This resulted in a morphological, anatomical and biochemical disease phenotype that closely resembles the human condition. The homozygous sheep were found to have significantly reduced PPT1 enzyme activity and accumulate autofluorescent storage material, as is observed in CLN1 patients. Clinical signs included pronounced behavioral deficits as well as motor deficits and complete loss of vision, with a reduced lifespan of 17 ± 1 months at a humanely defined terminal endpoint. Magnetic resonance imaging (MRI) confirmed a significant decrease in motor cortical volume as well as increased ventricular volume corresponding with observed brain atrophy and a profound reduction in brain mass of 30% at necropsy, similar to alterations observed in human patients. In summary, we have generated the first CRISPR/Cas9 gene edited NCL model. This novel sheep model of CLN1 disease develops biochemical, gross morphological and in vivo brain alterations confirming the efficacy of the targeted modification and potential relevance to the human condition.
Propofol for colonoscopy is largely administered by anesthesiologists or anesthesiology nurses in the United States (US) and Europe. Endoscopist-directed administration of propofol (EDP) by ...nonanesthesiologists has recently been proposed, with potential savings of anesthetist reimbursement costs. We aimed to assess potential EDP-related benefit in a screening setting.
In a Markov model the total number of screening and follow-up colonoscopies in a cohort of 100 000 US subjects were estimated. Anesthetist-assisted colonoscopy was compared with an EDP strategy. Model outputs were projected onto the 50 - 80-year-old US population, assuming 27 % as the current uptake for colonoscopy screening. Anesthetist costs were estimated using the mean reimbursement for the corresponding Medicare code (≥ 65-year-olds) and from commercial insurance information (50 - 64-year-olds). The proportion of colonoscopies with anesthesiologist assistance was estimated from the Medicare database. Mean nurse salary was used to estimate the cost of a 2-week EDP training. The absolute number of US endoscopists was estimated by inflating by 33 % the number of board-certified gastroenterologists. No EDP mortality was assumed in the reference scenario, and 0.0008 % mortality in the sensitivity analysis. US census data were adopted. Analogous inputs were used for France to assess EDP-related benefit in a European country.
EDP training for 17 166 nurses (one for each US endoscopist) showed a cost of $ 47 million. Cost estimates for anesthesiologist assistance for colonoscopy were $ 95 (Medicare) and $ 450 (non-Medicare commercial insurance), with 34.8 % of colonoscopies requiring anesthesiologist assistance. US implementation of an EDP policy showed a 10-year saving of $ 3.2 billion (Monte Carlo analysis 5 - 95 % percentiles $ 2.7 - $ 11.9 billion). In the sensitivity analysis, assuming 50 % of colonoscopies were anesthetist-assisted showed an EDP benefit of $ 4.6 billion. Assuming a 0.0008 % mortality rate, the incremental cost - effectiveness of anesthetist-assisted colonoscopy versus an EDP policy was $ 1.5 million per life-year gained, supporting EDP as the optimal choice. A 31-fold increase of EDP-related mortality or a 17-fold cost reduction for anesthetist-assisted colonoscopy was required for EDP to become not cost-effective in this scenario. Implementation of an EDP policy in France, within a guaiac-fecal occult blood test (g-FOBT) screening program, was estimated to save € 0.8 billion in 10 years.
The absolute economic benefit of EDP implementation in a screening setting is probably substantial with 10-year savings of $3.2 billion in the US and €0.8 billion in France. The impact of an eventual EDP-related mortality on EDP cost - effectiveness seems marginal. The huge economic and medical resources entailed by anesthetist-assisted colonoscopy could be more efficiently invested in other clinical fields.
Background
This study aimed to assess how the prevalence and growth rates of small and medium abdominal aortic aneurysms (AAAs) (3·0–5·4 cm) have changed over time in men aged 65 years, and to ...evaluate long‐term outcomes in men whose aortic diameter is 2·6–2·9 cm (subaneurysmal), and below the standard threshold for most surveillance programmes.
Methods
The Gloucestershire Aneurysm Screening Programme (GASP) started in 1990. Men aged 65 years with an aortic diameter of 2·6–5·4 cm, measured by ultrasonography using the inner to inner wall method, were included in surveillance. Aortic diameter growth rates were estimated separately for men who initially had a subaneurysmal aorta, and those who had a small or medium AAA, using mixed‐effects models.
Results
Since 1990, 81 150 men had ultrasound screening for AAA (uptake 80·7 per cent), of whom 2795 had an aortic diameter of 2·6–5·4 cm. The prevalence of screen‐detected AAA of 3·0 cm or larger decreased from 5·0 per cent in 1991 to 1·3 per cent in 2015. There was no evidence of a change in AAA growth rates during this time. Of men who initially had a subaneurysmal aorta, 57·6 (95 per cent c.i. 54·4 to 60·7) per cent were estimated to develop an AAA of 3·0 cm or larger within 5 years of the initial scan, and 28·0 (24·2 to 31·8) per cent to develop a large AAA (at least 5·5 cm) within 15 years.
Conclusion
The prevalence of screen‐detected small and medium AAAs has decreased over the past 25 years, but growth rates have remained similar. Men with a subaneurysmal aorta at age 65 years have a substantial risk of developing a large AAA by the age of 80 years.
Growth rates unchanged but prevalence decreasing
Obesity and obstetric anaesthesia Saravanakumar, K.; Rao, S. G.; Cooper, G. M.
Anaesthesia,
January 2006, 2006, 2006-Jan, 2006-01-00, Letnik:
61, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Summary
The prevalence of obesity continues to increase despite preventive strategies. Obese parturients are at increased risk of having either concurrent medical problems or superimposed antenatal ...diseases such as pre‐eclampsia and gestational diabetes. Moreover, they have a tendency to labour abnormally contributing to increased instrumental delivery and Caesarean section. Obesity is a risk factor for anaesthesia related maternal mortality. Morbidly obese women must be considered as high‐risk and deserve an anaesthetic consultation during their antenatal care. The significant difficulty in administering epidural analgesia should not preclude their use in labour. A more liberalised use of regional techniques may be a means to further reduce anaesthesia‐related maternal mortality in the obese population. The mother's life should not be jeopardised to save a compromised fetus. Prophylactic placement of an epidural catheter when not contraindicated in labouring morbidly obese women would potentially decrease anaesthetic and perinatal complications associated with attempts at emergency provision of regional or general anaesthesia. Early mobilisation, aggressive chest physiotherapy and adequate pain control are essential components of effective postoperative care.
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