Roadmap: proton therapy physics and biology.

The treatment of cancer with proton radiation therapy was first suggested in 1946 followed by the first treatments in the 1950s. As of 2020, almost 200 000 patients have been treated with proton beams worldwide and the number of operating proton therapy (PT) facilities will soon reach one hundred. PT has long moved from research institutions into hospital-based facilities that are increasingly being utilized with workflows similar to conventional radiation therapy. While PT has become mainstream and has established itself as a treatment option for many cancers, it is still an area of active research for various reasons: the advanced dose shaping capabilities of PT cause susceptibility to uncertainties, the high degrees of freedom in dose delivery offer room for further improvements, the limited experience and understanding of optimizing pencil beam scanning, and the biological effect difference compared to photon radiation. In addition to these challenges and opportunities currently being investigated, there is an economic aspect because PT treatments are, on average, still more expensive compared to conventional photon based treatment options. This roadmap highlights the current state and future direction in PT categorized into four different themes, 'improving efficiency', 'improving planning and delivery', 'improving imaging', and 'improving patient selection'.

Publisher Correction: Groundwater Throughflow and Seawater Intrusion in High Quality Coastal Aquifers.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Groundwater Throughflow and Seawater Intrusion in High Quality Coastal Aquifers.

High quality coastal aquifer systems provide vast quantities of potable groundwater for millions of people worldwide. Managing this setting has economic and environmental consequences. Specific knowledge of the dynamic relationship between fresh terrestrial groundwater discharging to the ocean and seawater intrusion is necessary. We present multi- disciplinary research that assesses the relationships between groundwater throughflow and seawater intrusion. This combines numerical simulation, geophysics, and analysis of more than 30 years of data from a seawater intrusion monitoring site. The monitoring wells are set in a shallow karstic aquifer system located along the southwest coast of Western Australia, where hundreds of gigalitres of fresh groundwater flow into the ocean annually. There is clear evidence for seawater intrusion along this coastal margin. We demonstrate how hydraulic anisotropy will impact on the landward extent of seawater for a given groundwater throughflow. Our examples show how the distance between the ocean and the seawater interface toe can shrink by over 100% after increasing the rotation angle of hydraulic conductivity anisotropy when compared to a homogeneous aquifer. We observe extreme variability in the properties of the shallow aquifer from ground penetrating radar, hand samples, and hydraulic parameters estimated from field measurements. This motived us to complete numerical experiments with sets of spatially correlated random hydraulic conductivity fields, representative of karstic aquifers. The hydraulic conductivity proximal to the zone of submarine groundwater discharge is shown to be significant in determining the overall geometry and landward extent of the seawater interface. Electrical resistivity imaging (ERI) data was acquired and assessed for its ability to recover the seawater interface. Imaging outcomes from field ERI data are compared with simulated ERI outcomes derived from transport modelling with a range of hydraulic conductivity distributions. This process allows for interpretation of the approximate geometry of the seawater interface, however recovery of an accurate resistivity distribution across the wedge and mixing zone remains challenging. We reveal extremes in groundwater velocity, particularly where fresh terrestrial groundwater discharges to the ocean, and across the seawater recirculation cell. An overarching conclusion is that conventional seawater intrusion monitoring wells may not be suitable to constrain numerical simulation of the seawater intrusion. Based on these lessons, we present future options for groundwater monitoring that are specifically designed to quantify the distribution of; (i) high vertical and horizontal pressure gradients, (ii) sharp variations in subsurface flow velocity, (iii) extremes in hydraulic properties, and (iv) rapid changes in groundwater chemistry. These extremes in parameter distribution are common in karstic aquifer systems at the transition from land to ocean. Our research provides new insights into the behaviour of groundwater in dynamic, densely populated, and ecologically sensitive coastal environments found worldwide.

Laminar flow does not affect risk of prosthetic joint infection after primary total knee replacement in Asian patients.

BACKGROUND: The role of laminar flow (LAF) is contradictory with several studies failing to replicate risk reduction. The 2016 World Health Organization guidelines identified this lack of good comparative studies. AIM: To analyse the use of LAF and the incidence of prosthetic joint infections (PJIs) in Asian patients undergoing total knee replacement (TKR). METHODS: Patients who underwent standard cemented posterior-stabilized TKR from 2004 to 2014 were reviewed from a prospectively collected single-surgeon database. Revision, traumatic and/or inflammatory cases were excluded. The type of airflow used was identified. The technique and surgical protocol for all procedures were similar. Tourniquets and inserted drains were routinely used. Patellar resurfacing was not performed. Patients were followed up at the outpatient clinics at regular intervals up to two years. At each visit, the patient was assessed for the occurrence of PJI. FINDINGS: Of the 1028 procedures, 453 (44.1%) were performed in an LAF operating theatre (OT) whereas 575 (55.9%) were performed in a non-LAF OT. There were no significant differences between the two groups in terms of age, gender, or side of procedure. The overall incidence of PJI was 0.6% (N = 6). Three (50%) occurred in an LAF OT whereas three (50%) occurred in a non-LAF OT. This was not statistically significant. CONCLUSION: Laminar flow systems are costly to procure and maintain. With modern aseptic techniques, patient optimization, and use of prophylactic antibiotics, laminar flow does not appear to further reduce risk of PJI in Asian patients after TKR.

Proteolytic inactivation of nuclear alarmin high-mobility group box 1 by complement protease C1s during apoptosis.

Effective clearance of apoptotic cells by phagocytes prevents the release of intracellular alarmins and manifestation of autoimmunity. This prompt efferocytosis is complemented by intracellular proteolytic degradation that occurs within the apoptotic cells and in the efferosome of the phagocytes. Although the role of extracellular proteases in apoptotic cells clearance is unknown, the strong association of congenital C1s deficiency with Systemic Lupus Erythematosus highlights the protective nature that this extracellular protease has against autoimmunity. The archetypical role of serine protease C1s as the catalytic arm of C1 complex (C1qC1r2C1s2) involve in the propagation of the classical complement pathway could not provide the biological basis for this association. However, a recent observation of the ability of C1 complex to cleave a spectrum of intracellular cryptic targets exposed during apoptosis provides a valuable insight to the underlying protective mechanism. High-mobility group box 1 (HMGB1), an intracellular alarmin that is capable of inducing the formation of antinuclear autoantibodies and causes lupus-like conditions in mice, is identified as a novel potential target by bioinformatics analysis. This is verified experimentally with C1s, both in its purified and physiological form as C1 complex, cleaving HMGB1 into defined fragments of 19 and 12 kDa. This cleavage diminishes HMGB1 ability to enhance lipopolysaccharide mediated pro-inflammatory cytokines production from monocytes, macrophages and dendritic cells. Further mass spectrometric analysis of the C1 complex treated apoptotic cellular proteins demonstrated additional C1s substrates and revealed the complementary role of C1s in apoptotic cells clearance through the proteolytic cleavage of intracellular alarmins and autoantigens. C1 complex may have evolved as, besides the bacteriolytic arm of antibodies in which it activates the complement cascade, a tissue renewal mechanism that reduces the immunogenicity of apoptotic tissue debris and decreases the likelihood of autoimmunity.

Post-operative outcomes of atypical femoral subtrochanteric fracture in patients on bisphosphonate therapy.

Management of bisphosphonate-associated subtrochanteric fractures remains opinion- or consensus-based. There are limited data regarding the outcomes of this fracture. We retrospectively reviewed 33 consecutive female patients with a mean age of 67.5 years (47 to 91) who were treated surgically between May 2004 and October 2009. The mean follow-up was 21.7 months (0 to 53). Medical records and radiographs were reviewed to determine the post-operative ambulatory status, time to clinical and radiological union and post-fixation complications such as implant failure and need for second surgery. The predominant fixation method was with an extramedullary device in 23 patients. 25 (75%) patients were placed on wheelchair mobilisation or no weight-bearing initially. The mean time to full weight-bearing was 7.1 months (2.2 to 29.7). The mean time for fracture site pain to cease was 6.2 months (1.2 to 17.1). The mean time to radiological union was 10.0 months (2.2 to 27.5). Implant failure was seen in seven patients (23%, 95 confidence interval (CI) 11.8 to 40.9). Revision surgery was required in ten patients (33%, 95 CI 19.2 to 51.2). A large proportion of the patients required revision surgery and suffered implant failure. This fracture is associated with slow healing and prolonged post-operative immobility.

Detection of microscopic particles present as contaminants in latent fingerprints by means of synchrotron radiation-based Fourier transform infra-red micro-imaging.

Synchrotron radiation-based Fourier transform infra-red (SR-FTIR) micro-imaging has been developed as a rapid, direct and non-destructive technique. This method, taking advantage of the high brightness and small effective source size of synchrotron light, is capable of exploring the molecular chemistry within the microstructures of microscopic particles without their destruction at high spatial resolutions. This is in contrast to traditional "wet" chemical methods, which, during processing for analysis, often caused destruction of the original samples. In the present study, we demonstrate the potential of SR-FTIR micro-imaging as an effective way to accurately identify microscopic particles deposited within latent fingerprints. These particles are present from residual amounts of materials left on a person's fingers after handling such materials. Fingerprints contaminated with various types of powders, creams, medications and high explosive materials (3-nitrooxy-2,2-bis(nitrooxymethyl)propyl nitrate (PETN), 1,3,5-trinitro-1,3,5-triazinane (RDX), 2-methyl-1,3,5-trinitrobenzene (TNT)) deposited on various - daily used - substrates have been analysed herein without any further sample preparation. A non-destructive method for the transfer of contaminated fingerprints from hard-to-reach areas of the substrates to the place of analysis is also presented. This method could have a significant impact on forensic science and could dramatically enhance the amount of information that can be obtained from the study of fingerprints.

SU-D-211-06: The Effect of Motion in RapidArc Lung SBRT Delivery.

PURPOSE: RapidArc is routinely used for stereotactic radiotherapy for lung cancer. While treatment dose is optimized and calculated on a static CT image, the motion of the target in conjunction with the motion of the MLC may Result in a delivered dose deviating from the planed dose. In this study, we investigate the dosimetric consequences of the inter-play effect by simulating dynamic dose delivery on a dynamic CT dataset of real patients. METHODS: The target motion in 20 patients was analyzed and 5 patients with >10 mm motion were chosen for this study. The RapidArc plan for eachpatient is optimized on a free-breathing CT using 2 arcs. Inherent in each plan is data on the associated parameters such as timestamp, MLC leave position, gantry angle and delivered beam MUs for each control point. Simulated dynamic delivery is performed by associating these parameters with each of the breathing phases of the 4D-CT. The starting breathing phase is selected randomly for each of the two arcs. Dose from the derived partial plans associated with each phase of the 4D-CT dose is recalculated in Eclipse. Accumulation of dose is performed using deformable image registration from each phase of the 4D-CT to the exhale phase of the 4D-CT. RESULTS: The coverage of the GTV and PTV shows negligible variations from the interplay effect. But the Homogeneity Index is affected by the motion. The prescription isodose volume is smaller than what was from the treatment plan dose. There were both intra- and inter-fraction effects seen inthe OARs dose in some patients. CONCLUSIONS: We investigated the motioneffect in RapidArc Lung SBRT delivery in 5 patients. Negligible variations were shown for target coverage. However the motion effects were observed in high dose distribution and volume. Some OARs dose distributions were affected by the motion.

Assessing kidney function in Asia.

An equation for accurate estimation of the glomerular filtration rate (GFR) is vital for staging and directing the treatment of chronic kidney disease (CKD), which is a source of considerable morbidity and mortality around the world. The Modification of Diet for Renal Disease (MDRD) equation, which includes a racial coefficient, is commonly used. The MDRD equation has been validated in Caucasian populations, but modifying the racial coefficient for Asian countries has resulted in substantially different values that may not be due to race alone. Moreover, it is sometimes difficult to define race, particularly in multi-ethnic populations and among offspring of inter-ethnic marriages. Furthermore, the precision of the MDRD equation is poorer at the early stages of CKD. New markers, such as cystatin C, and new equations may be needed to accurately assess wider ranges of GFR in multi-ethnic countries. We review the development of GFR-estimating equations from an Asian perspective.

A novel alternative method for 3D visualisation in Parasitology: the construction of a 3D model of a parasite from 2D illustrations.

Three-dimensional (3D) models of the marginal hooks, dorsal and ventral anchors, bars and haptoral reservoirs of a parasite, Sundatrema langkawiense Lim & Gibson, 2009 (Monogenea) were developed using the polygonal modelling method in Autodesk 3ds Max (Version 9) based on two-dimensional (2D) illustrations. Maxscripts were written to rotate the modelled 3D structures. Appropriately orientated 3D haptoral hard-parts were then selected and positioned within the transparent 3D outline of the haptor and grouped together to form a complete 3D haptoral entity. This technique is an inexpensive tool for constructing 3D models from 2D illustrations for 3D visualisation of the spatial relationships between the different structural parts within organisms.

Aortic and mitral valve endocarditis caused by Gemella morbillorum in a haemodialysis patient.

Gemella morbillorum is part of the commensal flora of the upper respiratory tract, intestinal tract and genitourinary tract. On rare occasions, it causes endocarditis. We report a 67-year-old Chinese man with end-stage renal disease on maintenance intermittent haemodialysis, who developed Gemella morbillorum endocarditis complicated by severe aortic and mitral regurgitation. Most cases of Gemella morbillorum endocarditis have satisfactory outcomes with antibiotics or surgical treatment.

Tunneling resonances and coherence in an optical lattice.

The center-of-mass quantization of atoms trapped in a gray optical lattice is observed to manifest itself in the steady-state properties of the atoms. Modulations in the lifetime and macroscopic magnetization as a function of an applied B field are attributed to quantum mechanical tunneling resonances and are shown to exist only under conditions which afford spatial coherence of the trapped atoms over several lattice wells and coherence times that exceed the tunneling period.

A comparative study of third-order nonlinear optical properties of silver phenylacetylide and related compounds via ultrafast optical Kerr effect measurements.

A comparative study of the third-order nonlinear optical properties, via the newly developed heterodyned optical Kerr effect (OHD-OKE) measurements, of silver phenylacetylide and related compounds is reported. [AgC[triple bond]CC(6)H(5)](n) (1) was found to exhibit efficient third-order nonlinear optical susceptibility chi((3)) of 2.4 x 10(-14) esu, and second hyperpolarizability gamma of 9.07 x 10(-32) esu. These results are compared with those of two related silver phenylacetylide compounds, namely, a double salt, (silver phenylacetylide).(silver tert-butylthiolate) [AgC[triple bond]CC(6)H(5).AgS(t-C(4)H(9))](n) complex (2), and a cluster, triphenylphosphine silver phenylacetylide tetramer, [(C(6)H(5))(3)PAgC[triple bond]CC(6)H(5)](4) (3), as well as that of the related organic polymer polyphenylacetylene (4). These four compounds represent different types of phenylacetylide derivatives: 1 is an organometallic polymer, 2 a polymeric double salt, 3 a discrete metal cluster, and 4 an organic polymer. It was found that the third-order optical nonlinear response was enhanced by the incorporation of silver d electrons into the delocalized conjugated organic pi system, and its magnitude is highly dependent upon the extent of the pi delocalization. Specifically, the relative magnitudes of chi((3)) and gamma follow the order silver phenylacetylide polymer (1) > (silver phenylacetylide).(silver tert-butylthiolate) double salt (2) > polyphenylacetylene polymer (4) > tetrameric (triphenylphosphine silver phenylacetylide)(4) cluster (3). The observed trend may be attributed to the decreasing length of pi conjugation. It is interesting to note that the incorporation of Ag(I) into the polymeric framework of polyphenylacetylene enhances the chi((3)) by 25-fold for the same degree of polymerization (n = 7). The signs of chi((3)) and gamma, which are related to the response mechanisms, were found to be solvent dependent.

The Alvarado score and acute appendicitis.

INTRODUCTION: This is a retrospective study to assess the accuracy of the Alvarado score in predicting appendicitis for patients with right iliac fossa pain. MATERIALS AND METHODS: This is a retrospective study of consecutive patients with suspected appendicitis. The Alvarado score was computed from the admission notes and correlated with the final outcome of the patient. Patients discharged without surgery were reviewed in the outpatient's clinic to ascertain that they did not need surgery. RESULTS: There were 148 patients in the study and 63 had appendectomies with intention to treat appendicitis. The normal appendicectomy rate was 21%. The number of patients with score 1-4, 5-6, 7-8 and 9-10 were 46, 40, 44 and 18, respectively, while the number of appendicitis in each group were 0, 2 (5%), 30 (68%) and 18 (100%), respectively. The positive and negative predictive values of Alvarado's scores of 7 or more were 77% and 97.6%, respectively. CONCLUSION: Alvarado score is a useful tool in the diagnosis of appendicitis, especially at both ends of the scale.

Sequence analysis of a fish vitellogenin cDNA with a large phosvitin domain.

Vitellogenins (Vtg) are egg-yolk precursor proteins crucial for reproductive success in oviparous animals. We have cloned the first complete cichlid Vtg cDNA from the tilapia fish, Oreochromis aureus. This cDNA has the largest phosvitin (PV) domain amongst piscine Vtgs, being comparable to those of lamprey, Xenopus, and chicken. Thus, the size of PV is independent of the evolutionary advancement of a species. The closer interspecific relationship between O. aureus Vtg1 and Fundulus VtgII than the intraspecific relationship between Fundulus VtgI and II isoforms suggests that teleost ancestors had at least two Vtg isoforms. Contrary to the results of previous phylogenetic inference using Vtgs which indicate that insect lineage is most diverged and nematodes are closer to vertebrate lineage, our results show that nematodes and hexapods form two monophyletic sister groups. Another arthropod taxon, represented by a malacostracan crustacean, Penaeus japonicus, appears to be more closely related to the vertebrates than the hexapods.

Synthesis and Structure of [DB24C8)Na][Cd(SCN)3. Formation of a novel linear Cd...Cd...Cd chain with a mer-CdN3S3 coordination confirmation and new coiled [(DB24C8)Na]+ cation.

We report herein a novel coordination solid, [(DB24C8)Na][Cd(SCN)3] (6) (DB24C8 denotes dibenzo-24-crown-8), which exhibits a new type of [Cd(SCN)3-]infinity chain with two unusual stereochemical characteristics: (1) a mer-CdN3S3 coordination and (2) a linear Cd chain with a Cd...Cd...Cd angle of 180 degrees. In addition, the [(DB24C8)Na]+ monocation adopts a new structural type-a coiled structure-for the combination of crown ether DB24C8 and alkali metal Na+. The title compound crystallizes in a monoclinic unit cell of C2/c space group symmetry with lattice parameters a = 16.110(8) A, b = 20.380(5) A, c = 11.01(1) A, beta = 119.87(3) degrees, and Z = 4. The arrangement of the [Cd(SCN)3-](infinity) chains in the crystal lattice in the title compound is approximately hexagonal, creating triangular channels which are filled with [(DB24C8)Na]+ monocations. It was previously reasoned by us that the coiled [(DB24C8)Na]+ monocation, which lacks inversion or mirror symmetries, should enhance the tendency for the formation of the noncentrosymmetric space group of the title crystal, making it a potential second-order nonlinear optical crystal. Interestingly, however, the title compound crystallizes in a centrosymmetric space group (C2/c) and gives rise to no second harmonic generation (SHG). Previously known [Cd(SCN)3-](infinity) chains adopt fac-CdN3S3 coordination and a zigzag Cd chain configuration with a Cd...Cd...Cd angle of 165 degrees. The zigzag chains can align in either parallel or antiparallel fashion, resulting in efficient or no SHG effects, respectively. The linear Cd.Cd.Cd chain configuration observed in the title compound, on the other hand, makes it indistinguishable between parallel and antiparallel alignments. It is concluded that, to ensure the formation of noncentrosymmetric space groups, it is necessary to employ optically pure chiral cations as spacers and/or controllers. Furthermore, to enhance the nonlinear optical responses, [Cd(SCN)3-]infinity chains with fac-CdN3S3 coordination and parallel alignments of the zigzag Cd chains should be used.

Wide spectral range nonlinear optical crystals of one-dimensional coordination solids [Et4N][Cd(SCN)3] and [Et4N][Cd(SeCN)3] and the general design criteria for [R4N][Cd(XCN)3] (Where R = Alkyl and X = S, Se, Te) as NLO crystals.

We report herein two new nonlinear optical (NLO) crystals, [Et4N][Cd(XCN)3], where X = S (1) and Se (2), that are transparent from 220 to 3300 nm, covering the entire near-ultraviolet, the visible, and the near-infrared spectral regions and giving rise to a very wide and continuous optical window, which is useful for many frequency conversion applications. Both 1 and 2 exhibit highly efficient second harmonic generation (SHG) as measured via the Kurtz-Perry method. The corresponding [Me4N]+ salts, [Me4N][Cd(XCN)3 where X = S (3) and Se (4), show no SHG effects. All four structures adopt noncentrosymmetric space groups (Cmc2(1) for 1 and 2 and Pna2(1) for 3 and presumably 4) and are based on one-dimensional anionic [Cd(XCN)3-] infinity zigzag chains. However, a detailed analysis of the structures of [R4N][Cd(XCN)3], where R = Et, Me and X = S, Se revealed that the difference in the second-order nonlinear responses of the Et4N+ salts (1 and 2) and the Me4N+ salts (3 and 4) is attributable to the relative alignment of the [Cd(XCN)3-] infinity zigzag chains, being parallel in the crystals of 1 and 2 but antiparallel in the crystals of 3 and 4. Also reported, for the first time, are the synthesis and crystal structure of [Et4N][Cd(SeCN)3] (2). Compound 2 crystallizes in an orthorhombic unit cell of Cmc21 space group symmetry with lattice parameters of 9.938(1) A, 16.868(2) A, 11.054(1) A, and Z = 4. Other issues related to the molecular and crystal engineering of this class of NLO materials are also discussed.