Therapeutic radiation beam output and energy variation across clinics, technologies, and time.

Over the past several decades, a medical physics service group covering 35 clinical sites has provided routine monthly output and energy quality assurance for over 75 linear accelerators. Based on the geographical spread of these clinics and the large number of physicists involved in data acquisition, a systematic calibration procedure was established to ensure uniformity. A consistent measurement geometry and data collection technique is used across all machines for every calendar month, using a standardized set of acrylic slabs. Charge readings in acrylic phantoms are linked to AAPM's TG-51 formalism via a parameter denoted kacrylic , used to convert raw charge readings to machine output values. Statistical analyses of energy ratios and kacrylic values are presented. Employing the kacrylic concept with a uniform measurement geometry of similar acrylic blocks was found to be a reproducible and simple way of referencing a calibration completed in water under reference conditions and comparing to other machines, with the ability to alert physicists of outliers.

Rapid shifting of a deep magmatic source at Fagradalsfjall volcano, Iceland.

Recent Icelandic rifting events have illuminated the roles of centralized crustal magma reservoirs and lateral magma transport1-4, important characteristics of mid-ocean ridge magmatism1,5. A consequence of such shallow crustal processing of magmas4,5 is the overprinting of signatures that trace the origin, evolution and transport of melts in the uppermost mantle and lowermost crust6,7. Here we present unique insights into processes occurring in this zone from integrated petrologic and geochemical studies of the 2021 Fagradalsfjall eruption on the Reykjanes Peninsula in Iceland. Geochemical analyses of basalts erupted during the first 50 days of the eruption, combined with associated gas emissions, reveal direct sourcing from a near-Moho magma storage zone. Geochemical proxies, which signify different mantle compositions and melting conditions, changed at a rate unparalleled for individual basaltic eruptions globally. Initially, the erupted lava was dominated by melts sourced from the shallowest mantle but over the following three weeks became increasingly dominated by magmas generated at a greater depth. This exceptionally rapid trend in erupted compositions provides an unprecedented temporal record of magma mixing that filters the mantle signal, consistent with processing in near-Moho melt lenses containing 107-108 m3 of basaltic magma. Exposing previously inaccessible parts of this key magma processing zone to near-real-time investigations provides new insights into the timescales and operational mode of basaltic magma systems.

Intrahepatic Xenograft of Cutaneous T-Cell Lymphoma Cell Lines: A Useful Model for Rapid Biological and Therapeutic Evaluation.

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases primarily involving the skin that could have an aggressive course with circulating blood cells, especially in Sézary syndrome and transformed mycosis fungoides. So far, few CTCL cell lines have been adapted for in vivo experiments and their tumorigenicity has not been adequately assessed, hampering the use of a reproducible model for CTCL biological evaluation. In fact, both patient-derived xenografts and cell line xenografts at subcutaneous sites failed to provide a robust tool, because engraftment was dependent on mice strain and cell line subtype. Herein, we describe an original method of intrahepatic injection into adult NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ mice liver of both aggressive (My-La, HUT78, HH, MAC2A, and MAC2B) and indolent (FE-PD and MAC1) CTCL cell lines. Six of the seven CTCL cell lines were grafted with a high rate of success (80%). Moreover, this model provided a quick (15 days) and robust assay for in vivo evaluation of CTCL cell lines tumorigenicity and therapeutic response in preclinical studies. Such a reproducible model can be therefore used for further functional studies and in vivo drug testing.

VMAT testing for an Elekta accelerator.

Volumetric-modulated arc therapy (VMAT) has been shown to be able to deliver plans equivalent to intensity-modulated radiation therapy (IMRT) in a fraction of the treatment time. This improvement is important for patient immobilization/localization compliance due to comfort and treatment duration, as well as patient throughput. Previous authors have suggested commissioning methods for this modality. Here, we extend the methods reported for the Varian RapidArc system (which tested individual system components) to the Elekta linear accelerator, using custom files built using the Elekta iComCAT software. We also extend the method reported for VMAT commissioning of the Elekta accelerator by verifying maximum values of parameters (gantry speed, multileaf collimator (MLC) speed, and backup jaw speed), investigating: 1) beam profiles as a function of dose rate during an arc, 2) over/under dosing due to MLC reversals, and 3) over/under dosing at changing dose rate junctions. Equations for construction of the iComCAT files are given. Results indicate that the beam profile for lower dose rates varies less than 3% from that of the maximum dose rate, with no difference during an arc. The gantry, MLC, and backup jaw maximum speed are internally consistent. The monitor unit chamber is stable over the MUs and gantry movement conditions expected. MLC movement and position during VMAT delivery are within IMRT tolerances. Dose rate, gantry speed, and MLC speed are accurately controlled. Over/under dosing at junctions of MLC reversals or dose rate changes are within clinical acceptability.

Parasite limiting macrophages promote IL-17 secretion in naive bovine CD4⁺ T-cells during Neospora caninum infection.

Neospora caninum infects bovine hosts giving rise to pro-inflammatory immune responses that can result in foetal death or spontaneous abortion, this appears to be mediated by the actions of IFN-γ on cell activation and migration/trafficking. Yet successful vaccination or natural immunity is also strongly correlated with IFN-γ production. We utilised in vitro infection of bovine macrophages to prime naive T-cell responses. Naive T-cells in contact with infected macrophages produce both IFN-γ and IL-17 in a pattern that is dependent on whether the priming macrophage was protected or non-protected. Our results may explain the apparent dual role of IFN-γ during infection if a second major pro-inflammatory cytokine, IL-17, is produced simultaneously.

Toxoplasma gondii peroxiredoxin promotes altered macrophage function, caspase-1-dependent IL-1ß secretion enhances parasite replication.

Alternatively activated macrophages (AAM) are a key feature Th2 immunity and have been associated with a variety of roles during helminth infection. The role this cell subset plays in protozoan infection remain relatively unexplored, herein we describe the effects of a redox enzyme (rTgPrx) derived from Toxoplasma gondii on murine macrophage phenotype in vitro. RTgPrx has been previously associated with the maintainance of parasite oxidative balance. Here our experiments show that rTgPrx promotes AAM as indicated by high arginase-1 (arg-1), YM1 and FIZZ expression via both signal transducer and activator of transcription (STAT)6-dependent and -independent mechanisms. Additionally rTgPrx treatment reduced caspase-1 activity and IL-1ß secretion, while simultaneously increasing IL-10 release. Furthermore the in vitro replication of T. gondii (RH strain) was enhanced when macrophages were treated with rTgPrx. This is in contrast with the previously described effects of a Plasmodium berghei ANKA 2-cys-peroxiredoxin that promotes pro-inflammatory cytokine production. These results highlight the role of T. gondii derived redox enzymes as important immune modulators and potentially indicate a role for AAM in modulating immunopathology and promoting parasite replication during T. gondii infection.

Bidentate salicylaldiminato tin(II) complexes and their use as lactide polymerisation initiators.

A study of the reactions of several salicylaldimines (ortho-iminophenols) with Sn(NMe2)2 reveals that the sterics and electronics of the N-substituent play a principal role in determining the product mixture. Thus mono(chelate) tin(II) amides have only been isolated with bulky N-anilido substituents, including [2,4-X2-6-{CHN-2,6-iPr2C6H3}-C6H2O]Sn(-NMe2)]2, X = Cl, 1; X = I, 2 and [2,4-Cl2-6-{CHN-2,4,6-tBu3C6H2}-C6H2O]Sn(NMe2), 3. With smaller N-aryl and N-alkyl substituted salicylaldimines, mixtures of mono- and bis- chelate complexes are formed, even if the phenoxide ring bears large tert-butyl substituents. Further, when the anilido group bears electron-withdrawing substituents, the imino carbon is activated towards nucleophilic attack (as demonstrated by the formation of [2,4-tBu2-6-{CH(NMe2)N-2,4,6-Br3C6H2}-C6H2O]Sn, 4); no such reactivity has been observed when the halo substituents are located on the phenolic ring. The abilities of complexes 1-4 to initiate the ring-opening polymerisation of rac-lactide have also been studied. Complexes 1, 2 and 4 possess comparitively similar activities, but propagation with 3 is at least one order of magnitude slower, an observation rationalised in terms of steric congestion.

The reversible amination of tin(II)-ligated imines: latent initiators for the polymerization of rac-lactide.

The 1:1 reactions of nine potentially tridentate salicylaldimines with tin(II) diamides, Sn(NR2)2 (R = Me, Et, iPr, SiMe3) have been investigated. With Sn(NiPr2)2 and Sn(NTMS2)2, the anticipated products of amine elimination, iminophenoxy tin(II) mono(amide)s, are formed. However, for R = Me and R = Et, nucleophilic attack of the amide at the imino carbon occurs to generate tin(II) complexes of tetradentate, dianionic aminoamidophenoxide ligands. The transfer of the amide is shown to be reversible, with both alcoholysis and the initiation of rac-lactide polymerization apparently mediated by the terminal amide tautomer.

Tert-butylamidinate tin(ii) complexes: high activity, single-site initiators for the controlled production of polylactide.

The tin(ii) coordination chemistry of two monoanionic N,N'-bis(2,6-diisopropylphenyl)alkylamidinate ligands is described. Complexation studies with the acetamidinate, [MeC(NAr)(2)](-), (Ar = 2,6-(i)Pr(2)C(6)H(3)) are complicated by the side formation of the bis(amidinate) tin(ii) compound, [MeC(NAr)(2)](2)Sn. By contrast, the bulkier tert-butylamidinate, [(t)BuC(NAr)(2)](-), allows tin(ii) mono-halide, -alkoxide and -amide complexes to be isolated cleanly in high yields. Thus, the reaction of [(t)BuC(NAr)(2)]H with (n)BuLi and subsequent treatment with SnCl(2) generates [(t)BuC(NAr)(2)]SnCl, in ca. 70% yield. Reactions of with LiO(i)Pr, LiNMe(2) and LiNTMS(2) afford [(t)BuC(NAr)(2)]Sn(O(i)Pr), [(t)BuC(NAr)(2)]Sn(NMe(2)), and [(t)BuC(NAr)(2)]Sn(NTMS(2)), respectively. The molecular structures of complexes are reported. Complexes, and have been investigated as initiators for the ring-opening polymerisation of rac-lactide: and display characteristics of well-controlled polymerisation initiators, but high molecular weight polymer is observed with due to inefficient initiation, a consequence of the steric bulk of the NTMS(2) unit. Polymerisations with and are faster than for the corresponding beta-diketiminate tin(ii) complexes, consistent with the more open nature of the tin(ii) coordination sphere.

Mono- versus bis-chelate formation in triazenide and amidinate complexes of magnesium and zinc.

Magnesium and zinc complexes of the monoanionic ligands N,N'-bis(2,6-di-isopropylphenyl)triazenide, L1, N,N'-bis(2,6-di-isopropylphenyl)acetamidinate, L2, and N,N'-bis(2,6-di-isopropylphenyl)tert-butylamidinate, L3, have been synthesized, but only L3 possesses sufficient steric bulk to prevent bis-chelation. Hence, the reaction of L1H with excess ZnEt2 leads to the isolation of (L1)2Zn, 1; L1H also reacts with Bu2Mg in Et2O to afford (L1)2Mg(Et2O), 2. Similar reactivity is observed for L2H, leading to the formation of (L2)2Zn, 3, and (L2)2Mg, 4. The reaction of L2H with ZnR2 may also afford the tetranuclear aggregates {(L2)Zn2R2}2O, 5 (R=Me) and 6 (R=Et). By contrast, the tert-butylamidinate ligand was found to exclusively promote mono-chelation, allowing (L3)ZnCl(THF), 7, [(L3)Zn(micro-Cl)]2, 8, (L3)ZnN(SiMe3)2, 9, (L3)MgiPr(Et2O), 10, and (L3)MgiPr(THF), 11, to be isolated. X-ray crystallographic analyses of 1, 2, 3, 4, 5, 6, 8, and 10 indicate that the capacity of L3 to resist bis-chelation is due to greater occupation of the metal coordination sphere by the N-aryl substituents.

Coordination complexes bearing potentially tetradentate phenoxyamine ligands.

A series of metal complexes containing potentially tetradentate phenoxyamine ligands is described. The ligands are found to bind to main-group metals and first-row transition-metal centres with variable denticity depending upon the requirements of the particular metal centre. Bidentate [Al(III)], tridentate [Mg(II), Ca(II), Zn(II)] and tetradentate [K(I), Cr(III), Fe(II), Co(II)] binding modes have been established unambiguously through single-crystal X-ray structure determinations.

Study of ligand substituent effects on the rate and stereoselectivity of lactide polymerization using aluminum salen-type initiators.

A series of aluminum salen-type complexes [where salen is N,N'-bis(salicylaldimine)-1,2-ethylenediamine] bearing ligands that differ in their steric and electronic properties have been synthesized and investigated for the polymerization of rac-lactide. X-ray crystal structures on key precatalysts reveal metal coordination geometries intermediate between trigonal bipyramidal and square-based pyramidal. Both the phenoxy substituents and the backbone linker have a significant influence over the polymerization. Electron-withdrawing groups attached to the phenoxy donor generally gave an increased polymerization rate, whereas large ortho substituents generally slowed down the polymerization. The vast majority of the initiators afforded polylactide with an isotactic bias; only one exhibited a bias toward heteroselectivity. Isoselectivity generally increases with increased flexibility of the backbone linker, which is presumed to be better able to accommodate any potential steric clashes between the propagating polymer chain, the inserting monomer unit, and the substituents on the phenoxy donor.

Synthetic, structural, mechanistic, and computational studies on single-site beta-diketiminate tin(II) initiators for the polymerization of rac-lactide.

A family of tin(II) complexes supported by beta-diketiminate ligands has been investigated as initiators for the polymerization of rac-lactide. Kinetic studies reveal a first-order dependence on [lactide], but with a significant induction period. Linear plots of M(n) versus conversion and [M](o)/[I](o) versus conversion, along with narrow molecular weight distributions (typically 1.07-1.10), are indicative of well-controlled, "living" polymerizations. Less sterically hindered derivatives promote faster propagation than their bulky analogues, in accord with a more accessible active site. Enhanced rates of polymerization are observed for ligands bearing halogenated N-aryl substituents, a consequence of the more Lewis acidic nature of the Sn(II) centers. All of the initiators exhibit a similar bias toward heterotactic polylactide, which is attributed to a chain-end control mechanism influenced predominantly by the presence of the Sn 5s(2) lone pair of electrons rather than the steric or electronic properties of the beta-diketiminate ligand. The tin(II) isopropyl-(S)-lactate complex, ((Me)BDI(DIPP))SnOCH(Me)COO(i)Pr (14), has been synthesized as a model compound for the propagating species by treatment of ((Me)BDI(DIPP))Sn(NMe(2)) with isopropyl-(S)-lactate. An X-ray structure determination showed that the lactate ligand forms a five-membered chelate ring with a weak donor bond from the carbonyl oxygen atom to the tin center. A B3LYP density functional computational study indicates that insertion of the first lactide monomer into the tin(II) alkoxide bond is facile, with the induction period arising from a slower insertion of the second (and possibly third and fourth) monomer units.

Titanium-salen complexes as initiators for the ring opening polymerisation of rac-lactide.

A family of bis(iso-propoxide) titanium(IV) complexes supported by tetradentate Schiff base (salen) ligands has been synthesised and characterised, including a structural determination of N,N'-bis(6'-methylenimino-2',4'-di-tert-butylphenoxy)cyclohexyl-(1R,2R)-diamino titanium(IV) bis(iso-propoxide). Their suitability for initiating the ring-opening polymerisation of rac-lactide has been investigated. Polymerisation activities are shown to correlate with the electronic properties of the substituents within the salen ligand. In contrast to aluminium-salen initiators, electron-withdrawing substituents on the Schiff base ligand have a detrimental influence upon polymerisation activities, whereas the use of electron-donating alkoxy-functionalized ligands has allowed the highest recorded activity to date for a titanium-based initiator.

Redox control within single-site polymerization catalysts.

The activity of a single-site titanium-based lactide polymerization initiator supported by a ferrocenyl-derivatized salen ligand is shown to be modulated by a chemical redox switch; a substantially higher rate of propagation is found for the neutral catalyst compared to its oxidized dicationic ferrocenium counterpart.

Timeliness and task specification in designing for human factors in railway operations.

Human error is often related to flaws in system design which might have been avoided had greater attention been paid to human factors knowledge and methods as the system was developed. The paper considers the role of human factors in system design and argues that adopting an operational perspective in identifying human factors issues ensures that subsequent human factors advice is focused upon real needs and is consistent with how managers and engineers choose to manage their systems. It also considers the issue of timeliness of human factors input. Failure to consider human factors issues at a time when other design decisions are being taken often means that it is less straightforward to accommodate changes. Thus, managers and engineers may resist dealing effectively with potential human factors problems for reasons of cost and delay in meeting project milestones.

A computational analysis of the ring-opening polymerization of rac-lactide initiated by single-site beta-diketiminate metal complexes: defining the mechanistic pathway and the origin of stereocontrol.

The ring-opening polymerization of rac-lactide at a beta-diketiminate magnesium center, [HC{CMeN-2,6-(i)Pr(2)C(6)H(3)}(2)]Mg(OMe)(THF), has been investigated using a B3-LYP density functional procedure employing three different layers of basis set: 6-311G(3d) at the Mg center, 6-31G(d) for both the ligand skeleton and the monomer, and a STO-3G basis set at the bulky 2,6-diisopropylphenyl substituents. By studying the consecutive ring-opening of two lactide molecules, clear conclusions are drawn regarding both the mechanism of ring-opening and the origin of heterotactic stereocontrol observed with such initiators. Polymerization proceeds via two major transition states, an observation applicable to other coordinative initiator systems, with the highest energy transition state dictating the stereochemistry of monomer insertion. In the beta-diketiminate magnesium system, a detailed examination of the rate-limiting second transition state geometries reveals that heterotactic poly(lactic acid) arises via the minimization of several steric interactions, possibly reinforced by an attractive CH...pi interaction.

Unprecedented reversible migration of amide to schiff base ligands attached to tin: latent single-site initiators for lactide polymerization.

In an unprecedented transformation, amide ligands are found to attack the imine carbon centers of tridentate Schiff base ligands attached to tin. The process is reversible, and the resultant (masked) amide species can be exploited as latent single-site initiators for the controlled polymerization of rac-lactide.