Effects of flow forming parameters on dimensional accuracy in Cr-Mo-V steel tubes

Flow forming is a near-net shape forming process used to produce a range of tubular components. Advantages of the process include increased mechanical properties, grain refinement and high production rates. The cost effectiveness of the process stems from a reduction in input weight and a reduction in final machining time as compared to machine from solid routes. Careful selection of flow forming parameters, such as feed rate and spindle speed, is needed to ensure that the dimensional requirements of component design are met. The main purpose of this work was to explore the effects of machine parameters on geometrical outputs of flow formed trial parts in Cr-Mo-V steel, which is used in aerospace applications. Cr-Mo-V steel was flow formed in the annealed and the hardened and tempered conditions to assess the formability of the material across a range of input hardness. Results including inner diameter growth, formed wall thickness and material sectional hardness are presented. Forming trials were conducted at the Advanced Forming Research Centre on a WF STR600/3 flow former, which is equipped with force sensors on all three of the forming axes. The required forming loads are a significant aspect of managing tool life in an industrial setting, therefore the roller loads generated during forming have been studied. Experiments showed that there is a clear link between machine parameters and geometrical outputs. Slower feed rates and faster spindle speeds resulted in larger inner diameter growth and reduced wall thicknesses. Increased spindle speeds also caused a significant reduction in forming load. The hardness of the material was found to be proportional to the thickness reduction imposed on the trial parts in the annealed condition. Overall, it was observed that varying parameters in flow forming produced clear trends in the outputs, which can be used to predict tolerances in the design of components

Seven features of safety in maternity units: a framework based on multisite ethnography and stakeholder consultation

Background: Reducing avoidable harm in maternity services is a priority globally. As well as learning from mistakes, it is important to produce rigorous descriptions of ‘what good looks like’. Objective: We aimed to characterise features of safety in maternity units and to generate a plain language framework that could be used to guide learning and improvement. Methods: We conducted a multisite ethnography involving 401 hours of non-participant observations 33 semistructured interviews with staff across six maternity units, and a stakeholder consultation involving 65 semistructured telephone interviews and one focus group. Results: We identified seven features of safety in maternity units and summarised them into a framework, named For Us (For Unit Safety). The features include: (1) commitment to safety and improvement at all levels, with everyone involved; (2) technical competence, supported by formal training and informal learning; (3) teamwork, cooperation and positive working relationships; (4) constant reinforcing of safe, ethical and respectful behaviours; (5) multiple problem-sensing systems, used as basis of action; (6) systems and processes designed for safety, and regularly reviewed and optimised; (7) effective coordination and ability to mobilise quickly. These features appear to have a synergistic character, such that each feature is necessary but not sufficient on its own: the features operate in concert through multiple forms of feedback and amplification. Conclusions: This large qualitative study has enabled the generation of a new plain language framework—For Us—that identifies the behaviours and practices that appear to be features of safe care in hospital-based maternity units

Albendazole and antibiotics synergize to deliver short-course anti-Wolbachiacurative treatments in preclinical models of filariasis

Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia, a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles

TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium

Synthesis and biological evaluation of a new family of constrained azabicyclic homocholine analogues

A family of constrained acylated homocholine analogues have been synthesized, based on the azabicyclic ring scaffold derived from a double-Mannich annulation of cyclic ketones. The short synthetic route allows generation of structural diversity including, variation in the carbocyclic ring size, bridgehead substitution, nitrogen substitution and the ester sidechain. Biological assays on selected analogues demonstrate these compounds are nicotinic acetylcholine receptor (nAChR) antagonists. Several analogues also bind to other neuronal transporter and receptor targets

The effect of transdiagnostic emotion-focused treatment on obsessive-compulsive symptoms in children and adolescents

Obsessive-compulsive disorder (OCD) commonly onsets in childhood. Given OCD's high comorbidity with other emotional disorders (e.g., depression, anxiety), transdiagnostic treatment that aims to enhance youth's tolerance and regulation of various negative emotions before starting exposure may facilitate simultaneous treatment of multiple comorbid symptoms. The current study examined the effects of transdiagnostic treatment in an open trial of clinical youth. Children and adolescents (N = 170) with any primary emotional disorder (e.g., an anxiety, depressive, or obsessive-compulsive spectrum disorder) started Unified Protocols for Transdiagnostic Treatment of Emotional Disorders in Children and Adolescents (UP–C/A) treatment. Youth (M age = 12; 50% female) were primarily white and Hispanic/Latinx. Youth and their parent(s) completed an intake and follow-up assessments (8, 16, and 24 weeks). The outcome measures were self- and parent-reported obsessive-compulsive symptoms (OCS), treatment engagement, and client satisfaction. Over the course of the UP-C/A, youths' OCS decreased significantly, across reporters, regardless of child age or gender. These findings provide preliminary support for utilizing the UP-C/A to treat OCS in youth. While these results do not imply equivalence with existent, exposure and response prevention treatments for pediatric OCD, it is possible that the flexible structure of the UP-C/A may be applied successfully to OCS. •We examined effects of transdiagnostic treatment on obsessive-compulsive symptoms.•Obsessive-compulsive symptoms decreased from baseline to 8, 16, and 24 weeks.•Significant changes were noted across both self and parent report of symptoms.•Neither age nor gender moderated obsessive-compulsive symptom change trajectories.•Treatment engagement and satisfaction was similar regardless of OCD diagnosis

Double-Mannich annulation of cyclic ketones using N,N-bis(ethoxymethyl)alkylamine reagents

N,N-Bis(ethoxymethyl)alkylamines function as effective reagents in the double-Mannich annulation of cyclic ketone substrates, providing efficient access to a series of azabicyclic ketones. These ring systems are a useful scaffold for the four-step synthesis of novel constrained homocholine analogues