“Value Engineering…?” – Changes During Construction

“Value Engineering” is a frequently found clause in Construction contracts in the USA, allowing contractor-initiated design changes. Misleading is the interpretation of “value engineering” to imply cost savings shared with the owner, and its implementation during construction, is problematic. It is not surprising that such a clause would simply be ignored because it involves changes in design, often major changes in very short time; and change is feared and vehemently resisted by all parties, owner, designer, and contractor. The problem may lie in the divergence and separation of the designer/engineer and builder/contractor; their priorities and incentives are very different. The engineer spends years, even decades, in design and prepares contract documents often without a deep-seated understanding of construction methods, including geotechnical construction. Even worse, given extensive computational advancements, the designer submits exaggerated code-based designs with excessive safety factors. As for the contractor, he often builds without full appreciation of design principles or regard for design engineers. Owner budget and schedule constraints (not commensurate with his demands) and the ever-increasing litigious climate have exacerbated the situation. Adverse and hostile relationship between the various groups is often the norm with extended disputes and claims, not to mention the costs these entail. Redesign to apply a new technology or optimization of an inferior design just before construction becomes unthinkable. Four case histories are presented

Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.

Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.GW, BM, SG, JC-U, AS, AG-M, CB, JJ, RL, AJL, SR, RS, LJ, VV-A, RM and RWW were funded by MedImmune; JP and VB were funded by AstraZeneca PLC; JW, RSA-L and JB were funded by NIHR Cambridge Biomedical Research Centre and Kidney Research UK; JS and JF were funded by Retrogenix Ltd

Using video-reflexive ethnography to capture the complexity of leadership enactment in the healthcare workplace

This research was part of LG’s Ph.D. research which was generously funded by NHS Education for Scotland through SMERC.Current theoretical thinking asserts that leadership should be distributed across many levels of healthcare organisations to improve the patient experience and staff morale. However, much healthcare leadership education focusses on the training and competence of individuals and little attention is paid to the interprofessional workplace and how its inherent complexities might contribute to the emergence of leadership. Underpinned by complexity theory, this research aimed to explore how interprofessional healthcare teams enact leadership at a micro-level through influential acts of organising. A whole (interprofessional) team workplace-based study utilising video-reflexive ethnography occurred in two UK clinical sites. Thematic framework analyses of the video data (video-observation and video-reflexivity sessions) were undertaken, followed by in-depth analyses of human–human and human–material interactions. Data analysis revealed a complex interprofessional environment where leadership is a dynamic process, negotiated and renegotiated in various ways throughout interactions (both formal and informal). Being able to “see” themselves at work gave participants the opportunity to discuss and analyse their everyday leadership practices and challenge some of their sometimes deeply entrenched values, beliefs, practices and assumptions about healthcare leadership. These study findings therefore indicate a need to redefine the way that medical and healthcare educators facilitate leadership development and argue for new approaches to research which shifts the focus from leaders to leadership.Publisher PDFPeer reviewe

The Rodin-Ohno hypothesis that two enzyme superfamilies descended from one ancestral gene: an unlikely scenario for the origins of translation that will not be dismissed

Background Because amino acid activation is rate-limiting for uncatalyzed protein synthesis, it is a key puzzle in understanding the origin of the genetic code. Two unrelated classes (I and II) of contemporary aminoacyl-tRNA synthetases (aaRS) now translate the code. Observing that codons for the most highly conserved, Class I catalytic peptides, when read in the reverse direction, are very nearly anticodons for Class II defining catalytic peptides, Rodin and Ohno proposed that the two superfamilies descended from opposite strands of the same ancestral gene. This unusual hypothesis languished for a decade, perhaps because it appeared to be unfalsifiable. Results The proposed sense/antisense alignment makes important predictions. Fragments that align in antiparallel orientations, and contain the respective active sites, should catalyze the same two reactions catalyzed by contemporary synthetases. Recent experiments confirmed that prediction. Invariant cores from both classes, called Urzymes after Ur = primitive, authentic, plus enzyme and representing ~20% of the contemporary structures, can be expressed and exhibit high, proportionate rate accelerations for both amino-acid activation and tRNA acylation. A major fraction (60%) of the catalytic rate acceleration by contemporary synthetases resides in segments that align sense/antisense. Bioinformatic evidence for sense/antisense ancestry extends to codons specifying the invariant secondary and tertiary structures outside the active sites of the two synthetase classes. Peptides from a designed, 46-residue gene constrained by Rosetta to encode Class I and II ATP binding sites with fully complementary sequences both accelerate amino acid activation by ATP ~400 fold. Conclusions Biochemical and bioinformatic results substantially enhance the posterior probability that ancestors of the two synthetase classes arose from opposite strands of the same ancestral gene. The remarkable acceleration by short peptides of the rate-limiting step in uncatalyzed protein synthesis, together with the synergy of synthetase Urzymes and their cognate tRNAs, introduce a new paradigm for the origin of protein catalysts, emphasize the potential relevance of an operational RNA code embedded in the tRNA acceptor stems, and challenge the RNA-World hypothesis. Reviewers This article was reviewed by Dr. Paul Schimmel (nominated by Laura Landweber), Dr. Eugene Koonin and Professor David Ardell

Alien Registration- Bedian, Soghig (Sanford, York County)

https://digitalmaine.com/alien_docs/2861/thumbnail.jp

Alien Registration- Bedian, Soghig (Sanford, York County)

https://digitalmaine.com/alien_docs/2861/thumbnail.jp

VRDN-001, a Novel IGF-1R Monoclonal Antibody for the Treatment of Thyroid Eye Disease (TED): a Proposed Adaptive Design for Exploratory Proof of Concept

Adaptive design of clinical trials allows for more efficiency and less subject burden than conventional trials in the exploration of effectiveness and safety of drugs. An adaptive strategy is a scheme that allows for prospectively planned modifications to one or more aspects of the design based on accumulated data from subjects within the trial as it is ongoing. Adaptation is planned before comparative analyses of trial data are conducted, allowing opportunities for modifications to the trial itself. VRDN-001 is a humanized IgG1κ monoclonal antibody that binds specifically and with high affinity to human insulin-like growth factor-1 receptor (IGF-1R) and inhibits receptor activation.VRDN-001 is a humanized IgG1κ monoclonal antibody that binds specifically and with high affinity to human insulin-like growth factor-1 receptor (IGF- 1R) and inhibits receptor activation

VRDN-002, a Second-Generation Insulin Like Growth Factor-1 Receptor (IGF-1R) Antagonist Antibody for Thyroid Eye Disease: Preclinical Pharmacokinetic Profile and Clinical Promise

VRDN-002 is a novel anti-IGF-1R antibody incorporating half-life extension modifications in its Fc region for treatment of Thyroid Eye Disease (TED), a condition driven by Thyroid Stimulating Hormone Receptor (TSHR) agonistic autoantibodies and crosstalk between TSHR and IGF-1R. We compared the pharmacokinetic (PK) parameters of VRDN-002 in cynomolgus monkeys to the marketed IGF-1R antibody, teprotumumab, to project potential human dosing regimens