Random noise in Diffusion Tensor Imaging, its Destructive Impact and Some Corrections

The empirical origin of random noise is described, its influence on DTI variables is illustrated by a review of numerical and in vivo studies supplemented by new simulations investigating high noise levels. A stochastic model of noise propagation is presented to structure noise impact in DTI. Finally, basics of voxelwise and spatial denoising procedures are presented. Recent denoising procedures are reviewed and consequences of the stochastic model for convenient denoising strategies are discussed

The primary glucose-lowering effect of metformin resides in the gut, not the circulation: Results from short-term pharmacokinetic and 12-week dose-ranging studies

Delayed-release metformin (Met DR) is formulated to deliver the drug to the lower bowel to leverage the gut-based mechanisms of metformin action with lower plasma exposure. Met DR was assessed in two studies. Study 1 compared the bioavailability of single daily doses of Met DR to currently available immediaterelease metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers. Study 2 assessed glycemic control in subjects with type 2 diabetes (T2DM) over 12 weeks. Research Design and Methods Study 1 was a phase 1, randomized, four-period crossover study in 20 subjects. Study 2 was a 12-week, phase 2, multicenter, placebo-controlled, dose-ranging study in 240 subjects with T2DM randomized to receive Met DR 600, 800, or 1,000 mg administered once daily; blinded placebo; or unblindedMet XR 1,000 or 2,000 mg (reference). Results The bioavailability of 1,000mg Met DR b.i.d. was ∼50% that of Met IR and Met XR (study 1). In study 2, 600, 800, and 1,000 mg Met DR q.d. produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with an ∼40% increase in potency compared with Met XR. The placebo-subtracted changes from baseline in HbA1c level at 12 weeks were consistent with changes in FPG levels. All treatments were generally well tolerated, and adverse events were consistent with Glucophage/ Glucophage XR prescribing information. Conclusions Dissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action

Newborn resuscitation and support of transition of infants at birth European Resuscitation Council Guidelines 2021

The European Resuscitation Council has produced these newborn life support guidelines, which are based on the International Liaison Committee on Resuscitation (ILCOR) 2020 Consensus on Science and Treatment Recommendations (CoSTR) for Neonatal Life Support. The guidelines cover the management of the term and preterm infant. The topics covered include an algorithm to aid a logical approach to resuscitation of the newborn, factors before delivery, training and education, thermal control, management of the umbilical cord after birth, initial assessment and categorisation of the newborn infant, airway and breathing and circulation support, communication with parents, considerations when withholding and discontinuing support.Developmen

Reply letter to: Intubation in neonatal resuscitation - compelling necessity or incalculable risk?

Developmen

Efficacy of labral repair, biceps tenodesis, and diagnostic arthroscopy for SLAP Lesions of the shoulder: a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Surgery for type II SLAP (superior labral anterior posterior) lesions of the shoulder is a promising but unproven treatment. The procedures include labral repair or biceps tenodesis. Retrospective cohort studies have suggested that the benefits of tenodesis include pain relief and improved function, and higher patient satisfaction, which was reported in a prospective non-randomised study. There have been no completed randomised controlled trials of surgery for type II SLAP lesions. The aims of this participant and observer blinded randomised placebo-controlled trial are to compare the short-term (6 months) and long-term (2 years) efficacy of labral repair, biceps tenodesis, and placebo (diagnostic arthroscopy) for alleviating pain and improving function for type II SLAP lesions.</p> <p>Methods/Design</p> <p>A double-blind randomised controlled trial are performed using 120 patients, aged 18 to 60 years, with a history for type II SLAP lesions and clinical signs suggesting type II SLAP lesion, which were documented by MR arthrography and arthroscopy. Exclusion criteria include patients who have previously undergone operations for SLAP lesions or recurrent shoulder dislocations, and ruptures of the rotator cuff or biceps tendon. Outcomes will be assessed at baseline, three, six, 12, and 24 months. Primary outcome measures will be the clinical Rowe Score (1988-version) and the Western Ontario Instability Index (WOSI) at six and 24 months. Secondary outcome measures will include the Shoulder Instability Questionnaire (SIQ), the generic EuroQol (EQ-5 D and EQ-VAS), return to work and previous sports activity, complications, and the number of reoperations.</p> <p>Discussion</p> <p>The results of this trial will be of international importance and the results will be translatable into clinical practice.</p> <p>Trial Registration</p> <p><b>[ClinicalTrials.gov NCT00586742]</b></p

Further investigation of the role of HLA-DPB1 in adult Hodgkin's disease (HD) suggests an influence on susceptibility to different HD subtypes

It has been suggested in a number of studies that susceptibility to adult Hodgkin's disease (HD) is influenced by the HLA class II region, and specifically by alleles at the HLA-DPB1 locus. Since HD is diagnostically complex, it is not clear whether different HLA-DPB1 alleles confer susceptibility to different HD subtypes. To clarify this we have extended a previous study to type DPB1 alleles in 147 adult HD patients from a single centre. We have analysed patients with nodular sclerosing (NS), mixed cellularity (MC) or lymphocyte predominant (LP) HD, and gender in relation to HLA-DPB1 type, in comparison with 183 adult controls. The results confirmed previously reported associations of DPB1*0301 with HD susceptibility (relative risk (RR) = 1.42; 95% confidence interval (CI) 0.86-2.36) and DPB1*0201 with resistance to HD (RR = 0.49; CI 0.27-0.90). However, analysis by HD subtype and gender showed that *0301-associated susceptibility was confined to females with HD (RR = 2.46; CI 1.02-5.92), and *0201-associated resistance to females with NS-HD (RR = 0.28; CI 0.10-0.79). Susceptibility to NS-HD was also associated in females with *1001 (RR = 11.73; CI 1.32-104.36), and resistance with *1101 (RR = 0.08; CI 0.01-0.65). In contrast, susceptibility to LP-HD was associated in males with *2001 (RR = 32.14; CI 3.17-326.17), and to MC-HD with *3401 (RR = 16.78; CI 2.84-99.17). Comparison of DPB1-encoded polymorphic amino-acid frequencies in patients and controls showed that susceptibility to MC-HD was associated with Leucine at position 35 of DPB1 (RR = 8.85; CI 3.04-25.77), Alanine-55 (RR = 15.17; CI 2.00-115.20) and Valine-84 (RR = 15.94; CI 3.55-71.49). In contrast, Glutamic acid 69 was significantly associated with resistance to MC-HD (RR = 0.14; CI 0.03-0.60). Certain DPB1 alleles and individual DPbeta1 polymorphic amino acid residues may thus affect susceptibility and resistance to specific HD subtypes. This may be through their influence on the binding of peptides derived from an HD-associated infectious agent, and the consequent effect on immune responses to the agent

X-Linked Genes and Risk of Orofacial Clefts: Evidence from Two Population-Based Studies in Scandinavia

Background: Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers. Methodology/Principal Findings: We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample. Conclusions: The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits

Analysis of the Effects of Polymorphism on Pollen Profilin Structural Functionality and the Generation of Conformational, T- and B-Cell Epitopes

An extensive polymorphism analysis of pollen profilin, a fundamental regulator of the actin cytoskeleton dynamics, has been performed with a major focus in 3D-folding maintenance, changes in the 2-D structural elements, surface residues involved in ligands-profilin interactions and functionality, and the generation of conformational and lineal B- and T-cell epitopes variability. Our results revealed that while the general fold is conserved among profilins, substantial structural differences were found, particularly affecting the special distribution and length of different 2-D structural elements (i.e. cysteine residues), characteristic loops and coils, and numerous micro-heterogeneities present in fundamental residues directly involved in the interacting motifs, and to some extension these residues nearby to the ligand-interacting areas. Differential changes as result of polymorphism might contribute to generate functional variability among the plethora of profilin isoforms present in the olive pollen from different genetic background (olive cultivars), and between plant species, since biochemical interacting properties and binding affinities to natural ligands may be affected, particularly the interactions with different actin isoforms and phosphoinositides lipids species. Furthermore, conspicuous variability in lineal and conformational epitopes was found between profilins belonging to the same olive cultivar, and among different cultivars as direct implication of sequences polymorphism. The variability of the residues taking part of IgE-binding epitopes might be the final responsible of the differences in cross-reactivity among olive pollen cultivars, among pollen and plant-derived food allergens, as well as between distantly related pollen species, leading to a variable range of allergy reactions among atopic patients. Identification and analysis of commonly shared and specific epitopes in profilin isoforms is essential to gain knowledge about the interacting surface of these epitopes, and for a better understanding of immune responses, helping design and development of rational and effective immunotherapy strategies for the treatment of allergy diseases. [EN]This study was supported by the following European Regional Development Fund co-financed grants: MCINN BFU 2004-00601/BFI, BFU 2008-00629, BFU2011-22779, CICE (Junta de Andalucía) P2010-CVI15767, P2010-AGR6274 and P2011-CVI-7487, and by the coordinated project Spain/Germany MEC HA2004-0094. JCJ-L thanks Spanish CSIC and the European Marie Curie research program for his I3P-BPD-CSIC, and PIOF-GA-2011-301550 grants, respectively.Peer reviewe