Genetics of osteoarthritis.

Osteoarthritis genetics has been transformed in the past decade through the application of large-scale genome-wide association scans. So far, over 100 polymorphic DNA variants have been associated with this common and complex disease. These genetic risk variants account for over 20% of osteoarthritis heritability and the vast majority map to non-protein coding regions of the genome where they are presumed to act by regulating the expression of target genes. Statistical fine mapping, in silico analyses of genomics data, and laboratory-based functional studies have enabled the identification of some of these targets, which encode proteins with diverse roles, including extracellular signaling molecules, intracellular enzymes, transcription factors, and cytoskeletal proteins. A large number of the risk variants correlate with epigenetic factors, in particular cartilage DNA methylation changes in cis, implying that epigenetics may be a conduit through which genetic effects on gene expression are mediated. Some of the variants also appear to have been selected as humans adapted to bipedalism, suggesting that a proportion of osteoarthritis genetic susceptibility results from antagonistic pleiotropy, with risk variants having a positive role in joint formation but a negative role in the long-term health of the joint. Although data from an osteoarthritis genetic study has not yet directly led to a novel treatment, some of the osteoarthritis associated genes code for proteins that have available therapeutics. Genetic investigations are therefore revealing fascinating fundamental insights into osteoarthritis and can expose options for translational intervention.

Efficacy of mupirocin, neomycin and octenidine for nasal Staphylococcus aureus decolonisation: a retrospective cohort study.

BACKGROUND: Periprosthetic joint infection (PJI) causes significant morbidity. Methicillin sensitive Staphylococcus aureus (MSSA) is the most frequent organism, and the majority are endogenous. Decolonisation reduces PJIs but there is a paucity of evidence comparing treatments. Aims; compare 3 nasal decolonisation treatments at (1) achieving MSSA decolonisation, (2) preventing PJI. METHODS: Our hospital prospectively collected data on our MSSA decolonisation programme since 2013, including; all MSSA carriers, treatment received, MSSA status at time of surgery and all PJIs. Prior to 2017 MSSA carriers received nasal mupirocin or neomycin, from August 2017 until August 2019 nasal octenidine was used. RESULTS: During the study period 15,958 primary hip and knee replacements were performed. 3200 (20.1%) were MSSA positive at preoperative screening and received decolonisation treatment, 698 mupirocin, 1210 neomycin and 1221 octenidine. Mupirocin (89.1%) and neomycin (90.9%) were more effective at decolonisation than octenidine (50.0%, P < 0.0001). There was no difference in PJI rates (P = 0.452). CONCLUSIONS: Mupirocin and neomycin are more effective than octenidine at MSSA decolonisation. There was poor correlation between the MSSA status after treatment (on day of surgery) and PJI rates. Further research is needed to compare alternative MSSA decolonisation treatments.

An asymptotic hyperbolic-elliptic model for flexural-seismic metasurfaces.

We consider a periodic array of resonators, formed from Euler-Bernoulli beams, attached to the surface of an elastic half-space. Earlier studies of such systems have concentrated on compressional resonators. In this paper, we consider the effect of the flexural motion of the resonators, adapting a recently established asymptotic methodology that leads to an explicit scalar hyperbolic equation governing the propagation of Rayleigh-like waves. Compared with classical approaches, the asymptotic model yields a significantly simpler dispersion relation, with closed-form solutions, shown to be accurate for surface wave-speeds close to that of the Rayleigh wave. Special attention is devoted to the effect of various junction conditions joining the beams to the elastic half-space which arise from considering flexural motion and are not present for the case of purely compressional resonators. Such effects are shown to provide significant and interesting features and, in particular, the choice of junction conditions dramatically changes the distribution and sizes of stop bands. Given that flexural vibrations in thin beams are excited more readily than compressional modes and the ability to model elastic surface waves using the scalar wave equation (i.e. waves on a membrane), the paper provides new pathways towards novel experimental set-ups for elastic metasurfaces.

Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus.

Lipoprotein associated phospholipase A2 (Lp-PLA2) modulates low-density lipoprotein (LDL) oxidation by hydrolysing oxidised phospholipids present on particle surfaces. We investigated whether Lp-PLA2 activity and PLA2G7 A379V genotype were related to mediators of atherosclerosis in a diabetic study. Plasma Lp-PLA2 activity (taken in men only) and A379V genotype were investigated with regards to metabolic syndrome (MS), UKPDS risk score, and oxidised LDL (oxLDL/LDL), in a cohort of Caucasian men and women (n=783, age 62.5+/-13.7 years). After adjustment for type of diabetes, CHD status, and statin use, those individuals with features defining the MS (WHO guidelines) had higher Lp-PLA2 activity (35.6+/-11.9 nmol/min/ml) compared to those without (33.0+/-10.8 nmol/min/ml) (p=0.02). Quartiles of UKPDS coronary heart disease (CHD) risk score were also positively associated with Lp-PLA2 activity (p=0.006, p=0.004 linear trend). Those men in the highest quartile of oxLDL/LDL level had the lowest Lp-PLA2 activity (31.3+/-10.5 nmol/min/ml) when compared to the middle two (32.3+/-9.8 and 35.9+/-10.9 nmol/min/ml, respectively) and lowest quartile (35.6 +/-12.5 nmol/min/ml; p=0.03, p=0.004 linear trend). There was no significant association between A379V genotype and Lp-PLA2 enzyme activity (p=0.34) or oxLDL/LDL (p=0.32). Lp-PLA2 activity is an independent predictor of CHD risk and MS in a sample of subjects with diabetes mellitus. The association of Lp-PLA2 activity with oxLDL/LDL suggests that Lp-PLA2 may be a modulating factor in the process of atherosclerosis.

Integration of radiotherapy planning systems and radiotherapy treatment equipment: 11 years experience.

PURPOSE: We have investigated the requirements, design, implementation, and operation of a computer-controlled medical accelerator with multileaf collimator (MLC), integrated with a radiation treatment-planning system (RTPS), and we report on the performance, benefits, and lessons learned from this experience. METHODS AND MATERIALS: In 1984 the University of Washington installed a computer-controlled radiation therapy machine (the Clinical Neutron Therapy System, or CNTS) with a multileaf collimator. Since the beginning of operation the control system computer has been connected by commercially available network hardware and software to three generations of radiation treatment-planning systems. Semiautomated setup and completely computerized check and confirm were incorporated into the system from the beginning of clinical operation in 1984. The system cannot deliver a patient treatment without a computer-prepared treatment plan. RESULTS: The CNTS has been in use for routine patient treatments for over 11 years. The cost of the network connection and software was an insignificant fraction of the facility cost. Operation has been efficient and reliable. Of the 441 machine-related session reschedulings (out of 18,432 sessions total) during the past 9 years, only 20 were due to problems with data transfer between the RTPS and CNTS, associated primarily with two incidents. Close integration with the treatment-planning system allows complex treatments to be delivered. Dramatic evolution of the departmental treatment-planning system has not required any changes or redesign of either the accelerator control system or the network connection. CONCLUSIONS: Our experience shows that a large degree of automation is possible with reasonable effort, by using well-known software and hardware design strategies. The lessons we have learned from this can be carried over into photon therapy now that photon accelerators with MLC facilities are commercially available.

Impact of a multileaf collimator on treatment morbidity in localized carcinoma of the prostate.

PURPOSE: To evaluate the effectiveness of variable multileaf collimation, three-dimensional treatment planning, and computer-controlled conformal radiation therapy of prostate cancer. METHODS AND MATERIALS: Two hundred and forty-five patients with locally advanced prostate cancer have completed treatment over a 9-year time span using a multileaf collimator and conformal treatment techniques on the University of Washington cyclotron. All patients had three-dimensional treatment planning with computed tomography scans in the treatment position, and had treatment fields individually shaped to the target volume with a continuously variable multileaf collimator. Treatment was delivered under computer control with network transfer of the multileaf collimator settings from the treatment planning computer to the cyclotron control system. RESULTS: The multileaf collimator combined with three-dimensional treatment planning results in elegant dose distributions. These neuron dose distributions resulted in a reduced local/regional tumor failure rate with no increase in complications when compared to control treatment with photons in a randomized trial. Neutron treatment delivered at other institutions without conformal beam shaping resulted in the same improvement in local-regional tumor control rates, but was associated with a significantly higher normal tissue complication rate than seen with conformal neutron beam delivery techniques (grade 3 and 4 cumulative late normal tissue toxicity rates of 39% vs. 10%, p = 0.0007). CONCLUSIONS: Conformal treatment of prostate cancer using a multileaf collimated neutron beam results in increased local/regional tumor control rates with low normal tissue toxicities. This experience is directly applicable to the conformal treatment of prostate cancer with photons.

Boron neutron capture therapy: a mechanism for achieving a concomitant tumor boost in fast neutron radiotherapy.

PURPOSE: For many years neutron radiation has been used to treat malignant disease both as fast neutron radiotherapy and as thermal neutron induced boron neutron capture therapy (BNCT). To date, these two approaches have been used independently of one another due to the large difference in neutron energies each employs. In this paper we discuss the potential application of BNCT to enhance the therapeutic effectiveness of a fast neutron radiotherapy beam. METHODS AND MATERIALS: Measurements are presented for the thermal neutron component that is spontaneously developed as the University of Washington fast neutron radiotherapy beam penetrates a water phantom. The biological effect of this thermalized component on cells "tagged" with boron-10 (10B) is modeled mathematically and the expected change in cell survival calculated. The model is then extended to estimate the effect this enhanced cell killing would have for increased tumor control. RESULTS: The basic predictions of the model on changes in cell survival are verified with in vitro measurements using the V-79 cell line. An additional factor of 10-100 in tumor cell killing appears achievable with currently available 10B carriers using our present neutron beam. A Poisson model is then used to estimate the change in tumor control this enhanced cell killing would produce in various clinical situations and the effect is sufficiently large so as to be clinically relevant. It is also demonstrated that the magnitude of the thermalized component can be increased by a factor of 2-3 with relatively simple changes in the beam generating conditions. CONCLUSION: BNCT may provide a means of enhancing the therapeutic effectiveness of fast neutron radiotherapy in a wide variety of clinical situations and is an area of research that should be aggressively pursued.

Neutron beam characteristics from 50 MeV protons on beryllium using a continuously variable multi-leaf collimator.

The dose distributional properties of a p(50) Be neutron beam using a continuously variable multi-leaf collimator are presented and compared with a 6 MV photon beam. The differences in physical dose delivery between these two radiation modalities are generally insignificant for radiation therapy, and stringent comparisons of neutron and photon treatments should therefore be possible. The flexibility in field shaping with the multi-leaf collimator opens new possibilities in the treatment of complex irregular target volumes. The collimator consists of 40 wedge-shaped leaves that are independently moved under computer control with their collimating surfaces always aligned with the effective radiation source to minimize the penumbra. The leaf collimator eliminates the need for handling of heavy insert collimators and beam blocks at the same time that it allows dynamic conformation therapy with neutrons.

Measurement of photon dose fraction in a neutron radiotherapy beam.

Photon dose fractions (PDFs) have been measured in and around a neutron radiotherapy beam with a tissue-equivalent proportional counter (TEPC) and with paired ion chambers. The PDFs were found to increase linearly with increasing field size and width depth in phantom. PDFs were shown to decrease with decreasing phantom size and to be larger in the shielded region of the phantom than in the direct beam. Uncertainties in the PDF values were estimated to be 10%-15% for the TEPC measurements but about 50% for the measurement made with ion chambers.

Dosimetric properties of neutrons from 21-MeV deuteron bombardment of a deuterium gas target.

Spectra, yields, average energies, and kerma rates in tissue of neutrons from 21-MeV deuteron bombardment of deuterium gas targets have been calculated for target thicknesses of 1, 3.5, and 5 MeV. A high pressure gas cell was constructed and was filled with 33 atm of D2 gas (equivalent to an energy loss of 3.5 MeV for 21-MeV deuterons); dose rate, dose buildup, and depth-dose properties of neutrons produced by the D(d,n) reaction were measured. Dosimetric properties of these neutrons are superior to those of neutrons from a thick Be target bombarded by a deuteron beam of the same energy.

Uniformity in dosimetry protocols for therapeutic applications of fast neutron beams.

In this supplement to both the American and the European protocols for clinical neutron dosimetry, new recommendations are given with respect to the basic physical parameters and experimental techniques employed. For neutron dosimetry, the air kerma or exposure calibration in a photon beam is the most suitable method for the calibration of tissue-equivalent ionization chambers until calibration in a standard neutron field becomes available. More recent data are recommended for the physical parameters required for the photon calibration as well as for the measurements in the neutron beam. Water is recommended as the reference phantom material due to its similarity in absorption and scattering properties to muscle. The resulting overall change in absorbed dose calculated according to this supplement, compared with the original protocols, will be smaller than about +/- 2% due to differences in the basic physical parameters. An additional change of several percent occurs at depth in a phantom as a result of the difference between water and the muscle-equivalent liquid formerly recommended as the reference phantom material.

Interim report: mammographic exposures at the breast cancer detection demonstration project screening centers.

In the interests of uniformly high radiological physics standards at ACS-NCI Breast Cancer Detection Demonstration Projects, measurements were made at 29 breast cancer screening clinics. These measurements were made throughout the country with equipment calibrated with standards traceable to National Bureau of Standards. Histograms which indicate the frequency distribution of exposures to the surface of a 6 cm breast for various machine/receptor combinations were prepared.

The effect of intracisternal injection of thyrotropin-releasing hormone on gastric and duodenal motility in the urethane-anaesthetized rat.

Intracisternal injection of thyrotropin-releasing hormone (TRH; 1-3 micrograms) caused an increase in gastric motility and usually an inhibition of duodenal motility. These effects were abolished by vagotomy and atropine. No inhibition was seen even after tone and motility had been restored to a point at which vagal stimulation could evoke profound inhibition of gastric and duodenal motility. It is concluded that TRH is a specific activator of enteric excitatory pathways and that duodenal inhibition seen in control animals is a consequence of gastro-duodenal inhibitory reflexes.