Chemoradiotherapy of locally-advanced non-small cell lung cancer: Analysis of radiation dose–response, chemotherapy and survival-limiting toxicity effects indicates a low α/β ratio

Purpose: To analyse changes in 2-year overall survival (OS2yr) with radiotherapy (RT) dose, dose-per-fraction, treatment duration and chemotherapy use, in data compiled from prospective trials of RT and chemo-RT (CRT) for locally-advanced non-small cell lung cancer (LA-NSCLC). Material and methods: OS2yr data was analysed for 6957 patients treated on 68 trial arms (21 RT-only, 27 sequential CRT, 20 concurrent CRT) delivering doses-per-fraction ≤4.0 Gy. An initial model considering dose, dose-per-fraction and RT duration was fitted using maximum-likelihood techniques. Model extensions describing chemotherapy effects and survival-limiting toxicity at high doses were assessed using likelihood-ratio testing, the Akaike Information Criterion (AIC) and cross-validation. Results: A model including chemotherapy effects and survival-limiting toxicity described the data significantly better than simpler models (p < 10−14), and had better AIC and cross-validation scores. The fitted α/β ratio for LA-NSCLC was 4.0 Gy (95%CI: 2.8–6.0 Gy), repopulation negated 0.38 (95%CI: 0.31–0.47) Gy EQD2/day beyond day 12 of RT, and concurrent CRT increased the effective tumour EQD2 by 23% (95%CI: 16–31%). For schedules delivered in 2 Gy fractions over 40 days, maximum modelled OS2yr for RT was 52% and 38% for stages IIIA and IIIB NSCLC respectively, rising to 59% and 42% for CRT. These survival rates required 80 and 87 Gy (RT or sequential CRT) and 67 and 73 Gy (concurrent CRT). Modelled OS2yr rates fell at higher doses. Conclusions: Fitted dose–response curves indicate that gains of ~10% in OS2yr can be made by escalating RT and sequential CRT beyond 64 Gy, with smaller gains for concurrent CRT. Schedule acceleration achieved via hypofractionation potentially offers an additional 5–10% improvement in OS2yr. Further 10–20% OS2yr gains might be made, according to the model fit, if critical normal structures in which survival-limiting toxicities arise can be identified and selectively spared

The PTW microSilicon diode: Performance in small 6 and 15 MV photon fields and utility of density compensation

PURPOSE: We have experimentally and computationally characterized the PTW microSilicon 60023-type diode's performance in 6 and 15 MV photon fields ≥5 × 5 mm2 projected to isocenter. We tested the detector on- and off-axis at 5 and 15 cm depths in water, and investigated whether its response could be improved by including within it a thin airgap. METHODS: Experimentally, detector readings were taken in fields generated by a Varian TrueBeam linac and compared with doses-to-water measured using Gafchromic film and ionization chambers. An unmodified 60023-type diode was tested along with detectors modified to include 0.6, 0.8, and 1.0 mm thick airgaps. Computationally, doses absorbed by water and detectors’ sensitive volumes were calculated using the EGSnrc/BEAMnrc Monte Carlo radiation transport code. Detector response was characterized using K^{fdin, 4cm}_{Qclin, 4cm}, a factor that corrects for differences in the ratio of dose-to-water to detector reading between small fields and the reference condition, in this study 5 cm deep on-axis in a 4 × 4 cm2 field. RESULTS: The greatest errors in measurements of small field doses made using uncorrected readings from the unmodified 60023-type detector were over-responses of 2.6% ± 0.5% and 5.3% ± 2.0% determined computationally and experimentally, relative to the reading-per-dose in the reference field. Corresponding largest errors for the earlier 60017-type detector were 11.9% ± 0.6% and 11.7% ± 1.4% over-responses. Adding even the thinnest, 0.6 mm, airgap to the 60023-type detector over-corrected it, leading to under-responses of up to 4.8% ± 0.6% and 5.0% ± 1.8% determined computationally and experimentally. Further, Monte Carlo calculations indicate that a detector with a 0.3 mm airgap would read correctly to within 1.3% on-axis. The ratio of doses at 15 and 5 cm depths in water in a 6 MV 4 × 4 cm2 field was measured more accurately using the unmodified 60023-type detector than using the 60017-type detector, and was within 0.3% of the ratio measured using an ion chamber. The 60023-type diode's sensitivity also varied negligibly as dose-rate was reduced from 13 to 4 Gy min–1 by decreasing the linac pulse repetition frequency, whereas the sensitivity of the 60017-type detector fell by 1.5%. CONCLUSIONS: The 60023-type detector performed well in small fields across a wide range of beam energies, field sizes, depths, and off-axis positions. Its response can potentially be further improved by adding a thin, 0.3 mm, airgap

Density compensated diodes for small field dosimetry: Comprehensive testing and implications for design

Purpose. In small megavoltage photon fields, the accuracies of an unmodified PTW 60017-type diode dosimeter and six diodes modified by adding airgaps of thickness 0.6-1.6 mm and diameter 3.6 mm have been comprehensively characterized experimentally and computationally. The optimally thick airgap for density compensation was determined, and detectors were micro-CT imaged to investigate differences between experimentally measured radiation responses and those predicted computationally. Methods. Detectors were tested on- and off-axis, at 5 and 15 cm depths in 6 and 15 MV fields ≥ 0.5 0.5 cm2. Computational studies were carried out using the EGSnrc/BEAMnrc Monte Carlo radiation transport code. Experimentally, radiation was delivered using a Varian TrueBeam linac and doses absorbed by water were measured using Gafchromic EBT3 film and ionization chambers, and compared with diode readings. Detector response was characterized via the formalism, choosing a 4 4 cm2 reference field. Results. For the unmodified 60017 diode, the maximum error in small field doses obtained from diode readings uncorrected by factors was determined as 11.9% computationally at +0.25 mm off-axis and 5 cm depth in a 15 MV 0.5 0.5 cm2 field, and 11.7% experimentally at -0.30 mm off-axis and 5 cm depth in the same field. A detector modified to include a 1.6 mm thick airgap performed best, with maximum computationally and experimentally determined errors of 2.2% and 4.1%. The 1.6 mm airgap deepened the modified dosimeter's effective point of measurement by 0.5 mm. For some detectors significant differences existed between responses in small fields determined computationally and experimentally, micro-CT imaging indicating that these differences were due to within-tolerance variations in the thickness of an epoxy resin layer. Conclusions. The dosimetric performance of a 60017 diode detector was comprehensively improved throughout 6 and 15 MV small photon fields via density compensation. For this approach to work well with good detector-to-detector reproducibility, tolerances on dense component dimensions should be reduced to limit associated variations of response in small fields, or these components should be modified to have more water-like densities

FMRFamide-Like Peptides (FLPs) Enhance Voltage-Gated Calcium Currents to Elicit Muscle Contraction in the Human Parasite Schistosoma mansoni

Schistosomes are amongst the most important and neglected pathogens in the world, and schistosomiasis control relies almost exclusively on a single drug. The neuromuscular system of schistosomes is fertile ground for therapeutic intervention, yet the details of physiological events involved in neuromuscular function remain largely unknown. Short amidated neuropeptides, FMRFamide-like peptides (FLPs), are distributed abundantly throughout the nervous system of every flatworm examined and they produce potent myoexcitation. Our goal here was to determine the mechanism by which FLPs elicit contractions of schistosome muscle fibers. Contraction studies showed that the FLP Tyr-Ile-Arg-Phe-amide (YIRFamide) contracts the muscle fibers through a mechanism that requires Ca2+ influx through sarcolemmal voltage operated Ca2+ channels (VOCCs), as the contractions are inhibited by classical VOCC blockers nicardipine, verapamil and methoxyverapamil. Whole-cell patch-clamp experiments revealed that inward currents through VOCCs are significantly and reversibly enhanced by the application of 1 µM YIRFamide; the sustained inward currents were increased to 190% of controls and the peak currents were increased to 180%. In order to examine the biochemical link between the FLP receptor and the VOCCs, PKC inhibitors calphostin C, RO 31–8220 and chelerythrine were tested and all produced concentration dependent block of the contractions elicited by 1 µM YIRFamide. Taken together, the data show that FLPs elicit contractions by enhancing Ca2+ influx through VOCC currents using a PKC-dependent pathway

Parents' views on care of their very premature babies in neonatal intensive care units: a qualitative study

Background The admission of a very premature infant to the neonatal intensive care unit (NICU) is often a difficult time for parents. This paper explores parents’ views and experiences of the care for their very premature baby on NICU. Methods Parents were eligible if they had a baby born before 32 weeks gestation and cared for in a NICU, and spoke English well. 32 mothers and 7 fathers were interviewed to explore their experiences of preterm birth. Although parents’ evaluation of care in the NICU was not the aim of these interviews, all parents spoke spontaneously and at length on this topic. Results were analysed using thematic analysis. Results Overall, parents were satisfied with the care on the neonatal unit. Three major themes determining satisfaction with neonatal care emerged: 1) parents’ involvement; including looking after their own baby, the challenges of expressing breast milk, and easy access to their baby; 2) staff competence and efficiency; including communication, experience and confidence, information and explanation; and 3) interpersonal relationships with staff; including sensitive and emotional support, reassurance and encouragement, feeling like an individual. Conclusions Determinants of positive experiences of care were generally consistent with previous research. Specifically, provision of information, support for parents and increasing their involvement in the care of their baby were highlighted by parents as important in their experience of care

Women’s reasons for, and experiences of, choosing a homebirth following a caesarean section

BACKGROUND: Caesarean section is rising in the developed world and vaginal birth after caesarean (VBAC) is declining. There are increased reports of women seeking a homebirth following a caesarean section (HBAC) in Australia but little is known about the reasons for this study aimed to explore women's reasons for and experiences of choosing a HBAC. METHODS: Twelve women participated in a semi-structured one-to-one interview. The interviews were digitally recorded, then transcribed verbatim. These data were analysed using thematic analysis. RESULTS: The overarching theme that emerged was ‘It’s never happening again’. Women clearly articulated why it [caesarean section] was never happening again under the following sub themes: ‘treated like a piece of meat’, ‘I was traumatised by it for years’, ‘you can smell the fear in the room’, ‘re-traumatised by the system’. They also described how it [caesarean section] was never happening again under the sub themes: ‘getting informed and gaining confidence’, ‘avoiding judgment through selective telling’, ‘preparing for birth’, ‘gathering support’ and ‘all about safety but I came first’. The women then identified the impact of their HBAC under the subthemes ‘I felt like superwoman’ and ‘there is just no comparison’. CONCLUSIONS: Birth intervention may cause physical and emotional trauma that can have a significant impact on some women. Inflexible hospital systems and inflexible attitudes around policy and care led some women to seek other options. Women report that achieving a HBAC has benefits for the relationship with their baby. VBAC policies and practices in hospitals need to be flexible to enable women to negotiate the care that they wish to have

Leveraging Rural Energy Investment for Parasitic Disease Control: Schistosome Ova Inactivation and Energy Co-Benefits of Anaerobic Digesters in Rural China

Cooking and heating remain the most energy intensive activities among the world's poor, and thus improved access to clean energies for these tasks has been highlighted as a key requirement of attaining the major objectives of the UN Millennium Development Goals. A move towards clean energy technologies such as biogas systems (which produce methane from human and animal waste) has the potential to provide immediate benefits for the control of neglected tropical diseases. Here, an assessment of the parasitic disease and energy benefits of biogas systems in Sichuan Province, China, is presented, highlighting how the public health sector can leverage the proliferation of rural energy projects for infectious disease control. ova) counted at the influent of two biogas systems were removed in the systems when adjusted for system residence time, an approximate 1-log removal attributable to sedimentation. Combined, these inactivation/removal processes underscore the promise of biogas infrastructure for reducing parasite contamination resulting from nightsoil use. When interviewed an average of 4 years after construction, villagers attributed large changes in fuel usage to the installation of biogas systems. Household coal usage decreased by 68%, wood by 74%, and crop waste by 6%. With reported energy savings valued at roughly 600 CNY per year, 2–3 years were required to recoup the capital costs of biogas systems. In villages without subsidies, no new biogas systems were implemented.Sustainable strategies that integrate rural energy needs and sanitation offer tremendous promise for long-term control of parasitic diseases, while simultaneously reducing energy costs and improving quality of life. Government policies can enhance the financial viability of such strategies by introducing fiscal incentives for joint sanitation/sustainable energy projects, along with their associated public outreach and education programs

The Syk Kinase SmTK4 of Schistosoma mansoni Is Involved in the Regulation of Spermatogenesis and Oogenesis

The signal transduction protein SmTK4 from Schistosoma mansoni belongs to the family of Syk kinases. In vertebrates, Syk kinases are known to play specialized roles in signaling pathways in cells of the hematopoietic system. Although Syk kinases were identified in some invertebrates, their role in this group of animals has not yet been elucidated. Since SmTK4 is the first Syk kinase from a parasitic helminth, shown to be predominantly expressed in the testes and ovary of adult worms, we investigated its function. To unravel signaling cascades in which SmTK4 is involved, yeast two-/three-hybrid library screenings were performed with either the tandem SH2-domain, or with the linker region including the tyrosine kinase domain of SmTK4. Besides the Src kinase SmTK3 we identified a new Src kinase (SmTK6) acting upstream of SmTK4 and a MAPK-activating protein, as well as mapmodulin acting downstream. Their identities and colocalization studies pointed to a role of SmTK4 in a signaling cascade regulating the proliferation and/or differentiation of cells in the gonads of schistosomes. To confirm this decisive role we performed biochemical and molecular approaches to knock down SmTK4 combined with a novel protocol for confocal laser scanning microscopy for morphological analyses. Using the Syk kinase-specific inhibitor Piceatannol or by RNAi treatment of adult schistosomes in vitro, corresponding phenotypes were detected in the testes and ovary. In the Xenopus oocyte system it was finally confirmed that Piceatannol suppressed the activity of the catalytic kinase domain of SmTK4. Our findings demonstrate a pivotal role of SmTK4 in gametogenesis, a new function for Syk kinases in eukaryotes

Interplay of Nkx3.2, Sox9 and Pax3 Regulates Chondrogenic Differentiation of Muscle Progenitor Cells

Muscle satellite cells make up a stem cell population that is capable of differentiating into myocytes and contributing to muscle regeneration upon injury. In this work we investigate the mechanism by which these muscle progenitor cells adopt an alternative cell fate, the cartilage fate. We show that chick muscle satellite cells that normally would undergo myogenesis can be converted to express cartilage matrix proteins in vitro when cultured in chondrogenic medium containing TGFß3 or BMP2. In the meantime, the myogenic program is repressed, suggesting that muscle satellite cells have undergone chondrogenic differentiation. Furthermore, ectopic expression of the myogenic factor Pax3 prevents chondrogenesis in these cells, while chondrogenic factors Nkx3.2 and Sox9 act downstream of TGFß or BMP2 to promote this cell fate transition. We found that Nkx3.2 and Sox9 repress the activity of the Pax3 promoter and that Nkx3.2 acts as a transcriptional repressor in this process. Importantly, a reverse function mutant of Nkx3.2 blocks the ability of Sox9 to both inhibit myogenesis and induce chondrogenesis, suggesting that Nkx3.2 is required for Sox9 to promote chondrogenic differentiation in satellite cells. Finally, we found that in an in vivo mouse model of fracture healing where muscle progenitor cells were lineage-traced, Nkx3.2 and Sox9 are significantly upregulated while Pax3 is significantly downregulated in the muscle progenitor cells that give rise to chondrocytes during fracture repair. Thus our in vitro and in vivo analyses suggest that the balance of Pax3, Nkx3.2 and Sox9 may act as a molecular switch during the chondrogenic differentiation of muscle progenitor cells, which may be important for fracture healing