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37, confidence interval 95%[-6.3;-2.4]; p<0.001). Moreover, individuals who had first-degree relative with alcohol dependence present smaller increase in BDNF levels when compared with individuals without family history (14.8 [-5.3;35.6] vs 35.3 [15.4;74.8]; p=0.005).

In summary, the variation of BDNF levels seems to be influenced by withdrawal in severe alcohol users. Also, positive family history of alcohol dependence could be a factor that influence the variation of this biomarker.

In summary, the variation of BDNF levels seems to be influenced by withdrawal in severe alcohol users. Also, positive family history of alcohol dependence could be a factor that influence the variation of this biomarker.While rare, incidents of inappropriate and/or unnecessary surgery do occur, so effective surveillance of surgical practice is required to ensure patient safety. This article explores the case of Ian Paterson, a consultant surgeon who was sentenced to 20 years in prison in 2017 for wounding with intent and unlawful wounding, primarily by undertaking inappropriate or unnecessary mastectomies. selleck chemicals The article details the main points of the Paterson case, with reference to the subsequent government-commissioned inquiry and its recommendations. It also outlines various strategies for enhancing patient safety, including applying human factors theory, improving auditing, and rationalising NHS and private healthcare. The author concludes that nurses have a crucial role in the surveillance of surgical practice and that combined reporting of surgeons' practice across NHS and private healthcare organisations is required.

The role of the advanced nurse practitioner (ANP) is not regulated in the UK, which has led to wide variation in the skills, competencies and academic qualifications of nurses using this title. Urgent treatment centres (UTCs) require a broad and experienced knowledge base to meet the demand of patients presenting with undifferentiated illnesses and injuries, which can be stressful and challenging.

To examine the perceptions and beliefs about ANP regulation, and to explore and discuss any ideas about proposed regulation.

The author used interpretative phenomenological analysis to uncover valuable insights into the experiences of two ANPs working in an UTC, and their beliefs around regulation of the ANP role.

Both ANPs had different backgrounds and qualifications yet still had similar perceptions and beliefs regarding the regulation of ANPs. link2 Five main themes were developed from the interview transcripts.

This study identified the need to consider the importance of ANPs' identity and the complex regulatory process required to standardise the role.

This study identified the need to consider the importance of ANPs' identity and the complex regulatory process required to standardise the role.The reaction space of the furanics-to-aromatics (F2A) conversion process for 5-hydroxymethylfurfural (HMF)-based platform chemicals has been explored both experimentally and by quantum chemistry methods. For the first time, a structure-activity relationship was established in furan-yne cycloaddition for a number of different HMF derivatives. Correlations between the activation energy of the cycloaddition stage and the structure of the substrates were established by molecular modeling methods. Analysis of the concerted and stepwise mechanisms of cycloaddition in the singlet and triplet electronic states of the molecular system was carried out. A series of biobased 7-oxanorbornadienes was obtained in the reaction with dimethyl acetylenedicarboxylate. Various methods of aromatization of the obtained [4+2] adducts have been examined. Rearrangement catalyzed by a Lewis acid leads to the formation of a phenol derivative, whereas reduction by diiron nonacarbonyl leads to the formation of functionalized benzene. Systematic study of the cycloaddition process has revealed a simple way to analyze and predict the relative reactivity of furanic substrates.

Up to 30% of hemophilia A patients develop inhibitory antibodies against the infused factor VIII (FVIII). The development of a deimmunized FVIII is an unmet high medical need. Although improved recombinant FVIII (rFVIII) products evolved within the last years, the immunogenicity has not been solved. A deimmunized FVIII could reduce the probability of inhibitor development, providing safer therapy.

To develop a deimmunized FVIII molecule by modifying major histocompatibility complex (MHC) class II presentation, leading to a functional but less immunogenic molecule.

We performed (1) in silico prediction of potentially immunogenic T cell epitopes and their modification by amino acid substitutions in the FVIII sequence, (2) evaluation of functional and structural similarity of the modified rFVIII to unmodified FVIII and registered products, and (3) confirmation of the reduced immunogenicity by in vitro testing.

A partially deimmunized fully functional FVIII molecule incorporating 19 amino acid substitutions was generated. The substitutions led to a reduction of the immunogenicity score, indicating a reduced immunogenicity based on in silico calculations. This was confirmed in an in vitro dendritic cell (DC)--T cell assay. Using this assay, cells from healthy donors proved the significantly reduced immunogenicity of the modified FVIII variant by revealing less proliferation of T helper cells to this variant than to the unmodified FVIII.

In silico predictions resulted in a partially deimmunized FVIII. This FVIII is fully functional and was demonstrated to be less immunogenic in in vitro testing. This approach may result in a reduction of the inhibitor risk for patients with hemophilia A.

In silico predictions resulted in a partially deimmunized FVIII. This FVIII is fully functional and was demonstrated to be less immunogenic in in vitro testing. This approach may result in a reduction of the inhibitor risk for patients with hemophilia A.Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady-state exposures (area under the concentration curve from 0 to 12-h [AUC0->12 h ]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m2 /dose) or a pharmacokinetically guided dose targeting an AUC0->12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in-target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.

Factor XII (FXII) is a serine protease that participates in the intrinsic coagulation pathway. Several studies have shown that plasma FXII exerts a deleterious role in cerebral ischemia and traumatic brain injury by promoting thrombo-inflammation. Nevertheless, the impact of FXII on neuronal cell fate remains unknown.

We investigated the role of FXII and FXIIa in neuronal injury and apoptotic cell death.

We tested the neuroprotective roles of FXII and FXIIa in an experimental model of neuronal injury induced by stereotaxic intracerebral injection of N-methyl-D-aspartic acid (NMDA) in vivo and in a model of apoptotic death of murine primary neuronal cultures through serum deprivation in vitro.

Here, we found that exogenous FXII and FXIIa reduce brain lesions induced by NMDA injection in vivo. Furthermore, FXII protects cultured neurons from apoptosis through a growth factor--like effect. This mechanism was triggered by direct interaction with epidermal growth factor (EGF) receptor and subsequent activation of this receptor. Interestingly, the "proteolytically" active and two-chain form of FXII, FXIIa, exerts its protective effects by an alternative signaling pathway. FXIIa activates the pro-form of hepatocyte growth factor (HGF) into HGF, which in turn activated the HGF receptor (HGFR) pathway.

This study describes two novel mechanisms of action of FXII and identifies neurons as target cells for the protective effects of single and two-chain forms of FXII. Therefore, inhibition of FXII in neurological disorders may have deleterious effects by preventing its beneficial effects on neuronal survival.

This study describes two novel mechanisms of action of FXII and identifies neurons as target cells for the protective effects of single and two-chain forms of FXII. Therefore, inhibition of FXII in neurological disorders may have deleterious effects by preventing its beneficial effects on neuronal survival.In this issue of FEBS Open Bio, Shen Li et al., in the laboratory of Hector L. Franco (University of North Carolina), provide a proof-of-principle solution for correcting all copies of a gene in the widely used MCF7 breast cancer cell line. The gene for the FOXA1 pioneer transcription factor is localised on chromosome 14, which is present at least 4-5 times in MCF7 cells. To achieve their goal, the authors used a 'classical' version of the CRISPR/Cas9 system. Both sgRNA and Cas9 components were expressed from a single vector, which also has a puromycin resistance cassette; this is an essential module for the chosen strategy, because it ensures expression of both sgRNA and Cas9 in selected cells. A targeting template in the form of nonlinearised plasmid was shown to have the best efficiency and was used to introduce a substitution at position 295 in the gene encoding FOXA1 to change a codon encoding lysine into a codon encoding glutamine (K295Q). The strategy suggested by Li and co-authors is an important development towards genome editing of multiple copy genes in a polyploid environment like cancer cells. One important application of the technique could be in creating models to study the role of single nucleotide polymorphisms in cancer progression and metastasis. Isogenic cancer lines carrying polymorphic variants of key drug targets could be used to optimise anticancer treatment protocols, laying a foundation for personalised therapy.

The assessment of muscle mass is a key determinant of the diagnosis of sarcopenia. We introduce for the first time an ultrasound imaging method for diagnosing sarcopenia based on changes in muscle geometric proportions.

Vastus lateralis muscle fascicle length (Lf) and thickness (Tm) were measured at 35% distal femur length by ultrasonography in a population of 279 individuals classified as moderately active elderly (MAE), sedentary elderly (SE) (n=109), mobility impaired elderly (MIE) (n=43), and in adult young controls (YC) (n=60). link3 The ratio of Lf/Tm was calculated to obtain an ultrasound index of the loss of muscle mass associated with sarcopenia (USI). In a subsample of elderly male individuals (n=76) in which corresponding DXA measurements were available (MAE, n=52 and SE, n=24), DXA-derived skeletal muscle index (SMI, appendicular limb mass/height

) was compared with corresponding USI values.

For both young and older participants, USI values were found to be independent of sex, height and body mass.