The role of endoscopy in bovine internal medicine - A review of current indication fields.

Endoscopy in bovine internal medicine has come a long way from the first profound research papers in the 1980s to its present-day use. This paper reviews the progress in the 2000s and identifies the main application fields for diagnostic and therapeutic use. Inclusion criteria for scientific papers and reports encompassed focus on endoscopic examination techniques in cattle in the field of internal medicine and publication in a peer reviewed journal (case report/review/original research paper/short communication). Only papers written in English or German language were considered. Studies on laparoscopy, theloscopy, and bronchoscopy show that endoscopic approaches often enable more rapid and accurate diagnosis and treatment options for single diseased animals as well as on a herd level. Oesophagoscopy, rumenoscopy, cystoscopy and thoracoscopy have also been increasingly studied and proven to be safe and effective tools with some limitations in diagnosing and/or treating various diseases in cattle. Scientific approaches explored the epidural space in cattle and comparison of different endoscope systems lead to recommendations for sinuscopy. Yet, this narrative literature review clearly shows that unlike in human medicine, where endoscopy as a minimally invasive technique is used for countless routine procedures every day, there is still some catching up to do in bovine medicine even though the potential of endoscopy in this field has been documented.

Sperm Toolbox-A selection of small molecules to study human spermatozoa.

Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the development of drugs that can either improve or inhibit fertility, we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in the Sperm Toolbox in several automated high-throughput assays that measure stimulation or inhibition of sperm motility or the acrosome reaction. We have assayed motility under non-capacitating and capacitating conditions to distinguish between pathways operating under these different physiological states. We also assayed cell viability to ensure any effects on sperm function are specific. A key advantage of our studies is that all compounds are assayed together in the same experimental conditions, which allows quantitative comparisons of their effects in complementary functional assays. We have combined the resulting datasets to generate fingerprints of the Sperm Toolbox compounds on sperm function. The data are included in an on-line R-based app for convenient querying.

Core PCP mutations affect short-time mechanical properties but not tissue morphogenesis in the Drosophila pupal wing.

How morphogenetic movements are robustly coordinated in space and time is a fundamental open question in biology. We study this question using the wing of Drosophila melanogaster, an epithelial tissue that undergoes large-scale tissue flows during pupal stages. Previously, we showed that pupal wing morphogenesis involves both cellular behaviors that allow relaxation of mechanical tissue stress, as well as cellular behaviors that appear to be actively patterned (Etournay et al., 2015). Here, we show that these active cellular behaviors are not guided by the core planar cell polarity (PCP) pathway, a conserved signaling system that guides tissue development in many other contexts. We find no significant phenotype on the cellular dynamics underlying pupal morphogenesis in mutants of core PCP. Furthermore, using laser ablation experiments, coupled with a rheological model to describe the dynamics of the response to laser ablation, we conclude that while core PCP mutations affect the fast timescale response to laser ablation they do not significantly affect overall tissue mechanics. In conclusion, our work shows that cellular dynamics and tissue shape changes during Drosophila pupal wing morphogenesis do not require core PCP as an orientational guiding cue.

Mycorrhiza-mediated recruitment of complete denitrifying Pseudomonas reduces N2O emissions from soil.

BACKGROUND: Arbuscular mycorrhizal fungi (AMF) are key soil organisms and their extensive hyphae create a unique hyphosphere associated with microbes actively involved in N cycling. However, the underlying mechanisms how AMF and hyphae-associated microbes may cooperate to influence N2O emissions from "hot spot" residue patches remain unclear. Here we explored the key microbes in the hyphosphere involved in N2O production and consumption using amplicon and shotgun metagenomic sequencing. Chemotaxis, growth and N2O emissions of isolated N2O-reducing bacteria in response to hyphal exudates were tested using in vitro cultures and inoculation experiments. RESULTS: AMF hyphae reduced denitrification-derived N2O emission (max. 63%) in C- and N-rich residue patches. AMF consistently enhanced the abundance and expression of clade I nosZ gene, and inconsistently increased that of nirS and nirK genes. The reduction of N2O emissions in the hyphosphere was linked to N2O-reducing Pseudomonas specifically enriched by AMF, concurring with the increase in the relative abundance of the key genes involved in bacterial citrate cycle. Phenotypic characterization of the isolated complete denitrifying P. fluorescens strain JL1 (possessing clade I nosZ) indicated that the decline of net N2O emission was a result of upregulated nosZ expression in P. fluorescens following hyphal exudation (e.g. carboxylates). These findings were further validated by re-inoculating sterilized residue patches with P. fluorescens and by an 11-year-long field experiment showing significant positive correlation between hyphal length density with the abundance of clade I nosZ gene. CONCLUSIONS: The cooperation between AMF and the N2O-reducing Pseudomonas residing on hyphae significantly reduce N2O emissions in the microsites. Carboxylates exuded by hyphae act as attractants in recruiting P. fluorescens and also as stimulants triggering nosZ gene expression. Our discovery indicates that reinforcing synergies between AMF and hyphosphere microbiome may provide unexplored opportunities to stimulate N2O consumption in nutrient-enriched microsites, and consequently reduce N2O emissions from soils. This knowledge opens novel avenues to exploit cross-kingdom microbial interactions for sustainable agriculture and for climate change mitigation. Video Abstract.

Coronary angiography after cardiac arrest without ST-elevation myocardial infarction: a network meta-analysis.

AIMS: This network meta-analysis aimed to assess the effect of early coronary angiography (CAG) compared with selective CAG (late and no CAG) for patients after out-of-hospital cardiac arrest without ST-elevation myocardial infarction (NSTE-OHCA). METHODS AND RESULTS: A systematic literature search was performed using the EMBASE, MEDLINE and Web of Science databases without restrictions on publication date. The last search was performed on 15 July 2022. Randomized controlled trials (RCTs) and non-randomized studies (NRS) comparing the effect of early CAG to selective CAG after NSTE-OHCA on survival and/or neurological outcomes were included. Meta-analyses were performed based on a DerSimonian-Laird random effects model. A total of 18 studies were identified by the literature search. After the exclusion of two studies due to high risk of bias, 16 studies (six RCTs, ten NRS) were included in the final analyses. Meta-analyses showed a statistically significant increase in survival after early CAG compared with selective CAG in the overall analysis [OR: 1.40, 95% confidence interval (CI): (1.12-1.76), P < 0.01, I2 = 68%]. This effect was lost in the subgroup analysis of RCTs [OR: 0.89, 95% CI: (0.73-1.10), P = 0.29, I2 = 0%]. Random effects model network meta-analysis of NRS based on a Bayesian method showed statistically significant increased survival after late compared with early CAG [OR: 4.20, 95% CI: (1.22, 20.91)]. CONCLUSION: The previously reported superiority of early CAG after NSTE-OHCA is based on NRS at high risk of selection and survivorship bias. The meta-analysis of RCTs does not support routinely performing early CAG after NSTE-OHCA.

Male contraceptive development: A medicinal chemistry perspective.

There is a need for non-hormonal contraceptives. One area that needs further investigation is the development of male contraceptives. Comparatively little is understood about potential drug targets in men to achieve a reversible contraceptive effect. In this article, we review the need for male contraceptives and some thoughts around the characteristics of a male contraceptive and the potential development pathway. We then discuss different potential approaches to discovering male contraceptives and then highlight potential targets that have been discussed in the literature.

Reliability and accuracy of dental MRI for measuring root canal length of incisors and canines: a clinical pilot study.

To evaluate whether high-resolution, non-contrast-enhanced dental MRI (dMRI) can reliably and accurately measure the canal length of incisors and canines compared with cone-beam computed tomography (CBCT). Three-Tesla dMRI was performed in 31 participants (mean age: 50.1 ± 14.2 years) with CBCT data. In total, 67 teeth were included (28 from the upper jaw and 39 from the lower jaw; 25 central incisors, 22 lateral incisors, and 20 canines). CBCT and dMRI datasets were reconstructed to visualize the root canal pathway in a single slice in the vestibulo-oral (V-O) and mesio-distal (M-D) direction. Root canal length was measured twice by two radiologists using dMRI and CBCT. Data were statistically analyzed by calculating intraclass correlation coefficients (ICCs) and performing Bland-Altman analysis. The reliability of dMRI measurements was excellent and comparable to that of CBCT measurements (intra-rater I/intra-rater II/inter-rater was 0.990/0.965/0.951 for dMRI vs. 0.990/0.994/0.992 for CBCT in the M-D direction and 0.991/0.956/0.967 for dMRI vs. 0.998/0.994/0.996 for CBCT in the V-O direction). According to Bland-Altman analysis, the mean (95% confidence interval) underestimation of root canal lengths was 0.67 mm (- 1.22 to 2.57) for dMRI and 0.87 mm (- 0.29 to 2.04) for CBCT in the M-D direction/V-O direction. In 92.5% of cases, dMRI measurements of canal length had an accuracy within 0-2 mm. Visualization and measurement of canal length in vivo using dMRI is feasible. The reliability of dMRI measurements was high and comparable to that of CBCT measurements. However, the spatial and temporal resolution of dMRI is lower than that of CBCT, which means dMRI measurements are less accurate than CBCT measurements. This means dMRI is currently unsuitable for measuring canal length in clinical practice.

Endodontic working length measurements of premolars and molars in high-resolution dental MRI: a clinical pilot study for assessment of reliability and accuracy.

OBJECTIVES: To prospectively assess the reliability and accuracy of high-resolution, dental MRI (dMRI) for endodontic working length (WL) measurements of premolars and molars under clinical conditions. MATERIALS AND METHODS: Three-Tesla dMRI was performed in 9 subjects who also had undergone cone-beam computed tomography (CBCT) (mean age: 47 ± 13.5 years). A total of 34 root canals from 12 molars (4/8, upper/lower jaw; 22 root canals) and 11 premolars (2/9 upper/lower jaw; 12 root canals) were included. CBCT and dMRI datasets were reconstructed to visualize the root canal in one single slice. Subsequently, two radiologists measured the root canal lengths in both modalities twice in blinded fashion. Reliability and accuracy for both modalities were assessed using intraclass correlation coefficients (ICCs) and Bland-Altman analysis, respectively. RESULTS: Reliability (intra-rater I/II; inter-rater) of dental MRI measurements was excellent and comparable to CBCT for premolars (0.993/0.900; 0.958 vs. 0.993/0.956; 0.951) and for molars (0.978/0.995; 0.986 vs. 0.992/0.996; 0.989). Bland-Altman analysis revealed a mean underestimation/bias (95% confidence interval) of dMRI measurements of 0.8 (- 1.44/3.05) mm for premolars and 0.4 (- 1.55/2.39) mm for molars. In up to 59% of the cases, the accuracy of dMRI for WL measurements was within the underestimation margin of 0 to 2 mm short of the apical foramen AF. CONCLUSIONS: In vivo demonstration and measurement of WL are feasible using dMRI. The reliability of measurements is high and equivalent to CBCT. Nonetheless, due to lower spatial resolution and longer acquisition time, the accuracy of dMRI is inferior to CBCT, impeding its current use for clinical treatment planning. CLINICAL RELEVANCE: dMRI is a promising radiation-free imaging technique. Its reliability for endodontic working length measurements is high, but its accuracy is not satisfactory enough yet.

Cut-down assisted percutaneous gastrostomy tube placement in morbidly obese patient.

Enteral and parenteral nutrition is primarily indicated in patients that lack adequate oral intake to support their metabolic needs. Percutaneous endoscopic gastrostomy (PEG) has become the preferred procedure of choice. With the increasing prevalence of obesity in the USA, there is a need for special interventions for PEG tube placements in overweight and obese patients. Some challenges that frequently arise with obese patients include sub-optimal transillumination, insufficient abdominal landmarks and inability to estimate the abdominal and gastric walls. We present a case of a patient with persistent dysphagia requiring enteral nutrition with an unconventional placement of a PEG tube given patient's large body habitus.

Compounds enhancing human sperm motility identified using a high-throughput phenotypic screening platform.

STUDY QUESTION: Can a high-throughput screening (HTS) platform facilitate male fertility drug discovery? SUMMARY ANSWER: An HTS platform identified a large number of compounds that enhanced sperm motility. WHAT IS KNOWN ALREADY: Several efforts to find small molecules modulating sperm function have been performed but none have used high-throughput technology. STUDY DESIGN, SIZE, DURATION: Healthy donor semen samples were used and samples were pooled (3-5 donors per pool). Primary screening was performed singly; dose-response screening was performed in duplicate (using independent donor pools). PARTICIPANTS/MATERIALS, SETTING, METHODS: Spermatozoa isolated from healthy donors were prepared by density gradient centrifugation and incubated in 384-well plates with compounds (6.25 µM) to identify those compounds with enhancing effects on motility. Approximately 17 000 compounds from the libraries, ReFRAME, Prestwick, Tocris, LOPAC, CLOUD and MMV Pathogen Box, were screened. Dose-response experiments of screening hits were performed to confirm the enhancing effect on sperm motility. Experiments were performed in a university setting. MAIN RESULTS AND THE ROLE OF CHANCE: From our primary single concentration screening, 105 compounds elicited an enhancing effect on sperm motility compared to dimethylsulphoxide-treated wells. Confirmed enhancing compounds were grouped based on their annotated targets/target classes. A major target class, phosphodiesterase inhibitors, were identified, in particular PDE10A inhibitors as well as number of compounds not previously known to enhance human sperm motility, such as those related to GABA signalling. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Although this approach provides data about the activity of the compound, it is only a starting point. For example, further substantive experiments are necessary to provide a more comprehensive picture of each compound's activity, the effect on the kinetics of the cell populations and subpopulations, and their potential mechanisms of action. Compounds have been tested with prepared donor spermatozoa, incubated under non-capacitating conditions, and only incubated with compounds for a relatively short period of time. Therefore, the effect of compounds under different conditions, for example in whole semen, for longer incubation times, or using samples from patient groups, may be different and require further study. All experiments were performed in vitro. WIDER IMPLICATIONS OF THE FINDINGS: This phenotypic screening assay identified a large number of compounds that increased sperm motility. In addition to furthering our understanding of human sperm function, for example identifying new avenues for discovery, we highlight potential compounds as promising start-point for a medicinal chemistry programme for potential enhancement of male fertility. Moreover, with disclosure of the results of screening, we present a substantial resource to inform further work in the field. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Bill and Melinda Gates Foundation, Scottish Funding Council and Scottish Universities Life Science Alliance. C.L.R.B. is Editor for RBMO. C.L.R.B. receives funding from Chief Scientists Office (Scotland), ESHRE and Genus PLC, consulting fees from Exscientia and lecture fees from Cooper Surgical and Ferring. S.M.d.S. is an Associate Editor of Human Reproduction, and an Associate Editor of Reproduction and Fertility. S.M.d.S. receives funding from Cooper Surgical and British Dietetic Society. No other authors declared a COI.

High-throughput phenotypic screening of the human spermatozoon.

Despite recent advances in male reproductive health research, there remain many elements of male infertility where our understanding is incomplete. Consequently, diagnostic tools and treatments for men with sperm dysfunction, other than medically assisted reproduction, are limited. On the other hand, the gaps in our knowledge of the mechanisms which underpin sperm function have hampered the development of male non-hormonal contraceptives. The study of mature spermatozoa is inherently difficult. They are a unique and highly specialised cell type which does not actively transcribe or translate proteins and cannot be cultured for long periods of time or matured in vitro. One large-scale approach to both increasing the understanding of sperm function and the discovery and development of compounds that can modulate sperm function is to directly observe responses to compounds with phenotypic screening techniques. These target agnostic approaches can be developed into high-throughput screening platforms with the potential to drastically increase advances in the field. Here, we discuss the rationale and development of high-throughput phenotypic screening platforms for mature human spermatozoa and the multiple potential applications these present, as well as the current limitations and leaps in our understanding and the capabilities needed to overcome them. Further development and use of these technologies could lead to the identification of compounds which positively or negatively affect sperm cell motility or function or novel platforms for toxicology or environmental chemical testing among other applications. Ultimately, each of these potential applications is also likely to increase the understanding within the field of sperm biology.

A comprehensive Monte Carlo study of out-of-field secondary neutron spectra in a scanned-beam proton therapy gantry room.

PURPOSE: To simulate secondary neutron radiation fields that had been measured at different relative positions during phantom irradiation inside a scanning proton therapy gantry treatment room. Further, to identify origin, energy distribution, and angular emission of the secondary neutrons as a function of proton beam energy. METHODS: The FLUKA Monte Carlo code was used to model the relevant parts of the treatment room in a scanned pencil beam proton therapy gantry including shielding walls, floor, major metallic gantry-components, patient table, and a homogeneous PMMA target. The proton beams were modeled based on experimental beam ranges in water and spot shapes in air. Neutron energy spectra were simulated at 0°, 45°, 90° and 135° relative to the beam axis at 2m distance from isocenter for monoenergetic 11×11cm2 fields from 200MeV, 140MeV, 75MeV initial proton beams, as well as for 118MeV protons with a 5cm thick PMMA range shifter. The total neutron spectra were scored for these four positions and proton energies. FLUKA neutron spectra simulations were crosschecked with Geant4 simulations using initial proton beam properties from FLUKA-generated phase spaces. Additionally, the room-components generating secondary neutrons in the room and their contributions to the total spectrum were identified and quantified. RESULTS: FLUKA and Geant4 simulated neutron spectra showed good general agreement with published measurements in the whole simulated neutron energy range of 10-10 to 103MeV. As in previous studies, high-energy (E≥19.6MeV) neutrons from the phantom are most prevalent along 0°, while thermalized (1meV≤E<0.4eV) and fast (100keV≤E<19.4MeV) neutrons dominate the spectra in the lateral and backscatter direction. The iron of the large bending magnet and its counterweight mounted on the gantry were identified as the most determinant sources of secondary fast-neutrons, which have been lacking in simplified room simulations. CONCLUSIONS: The results helped disentangle the origin of secondary neutrons and their dominant contributions and were strengthened by the fact that a cross comparison was made using two independent Monte Carlo codes. The complexity of such room model can in future be limited using the result. They may further be generalized in that they can be used for an assessment of neutron fields, possibly even at facilities where detailed neutron measurements and simulations cannot be performed. They may also help to design future proton therapy facilities and to reduce unwanted radiation doses from secondary neutrons to patients.

Global analysis reveals an environmentally driven latitudinal pattern in mushroom size across fungal species.

Although macroecology is a well-established field, much remains to be learned about the large-scale variation of fungal traits. We conducted a global analysis of mean fruit body size of 59 geographical regions worldwide, comprising 5340 fungal species exploring the response of fruit body size to latitude, resource availability and temperature. The results showed a hump-shaped relationship between mean fruit body size and distance to the equator. Areas with large fruit bodies were characterised by a high seasonality and an intermediate mean temperature. The responses of mutualistic species and saprotrophs were similar. These findings support the resource availability hypothesis, predicting large fruit bodies due to a seasonal resource surplus, and the thermoregulation hypothesis, according to which small fruit bodies offer a strategy to avoid heat and cold stress and therefore occur at temperature extremes. Fruit body size may thus be an adaptive trait driving the large-scale distribution of fungal species.

Use of dental MRI for radiation-free guided dental implant planning: a prospective, in vivo study of accuracy and reliability.

OBJECTIVES: To evaluate the accuracy and reliability of dental MRI for static guided implant surgery planning. MATERIALS AND METHODS: In this prospective study, a 0.4-mm isotropic, artifact-suppressed, 3T MRI protocol was used for implant planning and surgical guide production in participants in need of dental implants. Two dentists decided on treatment plan. Surgical guides were placed intraorally during a subsequent reference cone beam computed tomography (CBCT) scan. Inter-rater and inter-modality agreement were assessed by Cohen's kappa. For each participant, dental MRI and CBCT datasets were co-registered to determine three-dimensional and angular deviations between planned and surgically guided implant positions. RESULTS: Forty-five implants among 30 study participants were planned and evaluated (17 women, 13 men, mean age 56.9 ± 13.1 years). Inter-rater agreement (mean κ 0.814; range 0.704-0.927) and inter-modality agreement (mean κ 0.879; range 0.782-0.901) were both excellent for the dental MRI-based treatment plans. Mean three-dimensional deviations were 1.1 ± 0.7 (entry point) and 1.3 ± 0.7 mm (apex). Mean angular deviation was 2.4 ± 1.5°. CBCT-based adjustments of MRI plans were necessary for implant position in 29.5% and for implant axis in 6.8% of all implant sites. Changes were larger in the group with shortened dental arches compared with those for tooth gaps. Except for one implant site, all guides were suitable for clinical use. CONCLUSION: This feasibility study indicates that dental MRI is reliable and sufficiently accurate for surgical guide production. Nevertheless, more studies are needed to increase its accuracy before it can be used for implant planning outside clinical trials. KEY POINTS: • An excellent reliability for the dental MRI-based treatment plans as well as agreement between dental MRI-based and CBCT-based (reference standard) decisions were noted. • Ideal implant position was not reached in all cases by dental MRI plans. • For all but one implant site surgical guides derived from dental MRI were sufficiently accurate to perform implant placement (mean three-dimensional deviations were 1.1 ± 0.7 (entry point) and 1.3 ± 0.7 mm (apex); mean angular deviation was 2.4 ± 1.5°).

Radiation protection modelling for 2.5 Petawatt-laser production of ultrashort x-ray, proton and ion bunches: Monte Carlo model of the Munich CALA facility.

The 'Centre for Advanced Laser Applications' (CALA) is a new research institute for laser-based acceleration of electron beams for brilliant x-ray generation, laser-driven sub-nanosecond bunches of protons and heavy ions for biomedical applications like imaging and tumour therapy as well as for nuclear and high-field physics.The radiation sources emerging from experiments using the up to 2.5 petawatt laser pulses with 25 femtosecond duration will be mixed particle-species of high intensity, high energy and pulsed, thus posing new challenges compared to conventional radiation protection. Such worldwide pioneering laser experiments result in source characteristics that require careful a-priori radiation safety simulations.The FLUKA Monte-Carlo code was used to model the five CALA experimental caves, including the corridors, halls and air spaces surrounding the caves. Beams of electrons (<5 GeV), protons (<200 MeV),12C (<400MeV/u) and197Au (<10MeV/u) ions were simulated using spectra, divergences and bunch-charges based on expectations from recent scientific progress.Simulated dose rates locally can exceed 1.5 kSv h-1inside beam dumps. Vacuum pipes in the cave walls for laser transport and extraction channels for the generated x-rays result in small dose leakage to neighboring areas. Secondary neutrons contribute to most of the prompt dose rate outside caves into which the beam is delivered. This secondary radiation component causes non-negligible dose rates to occur behind walls to which large fluences of secondary particles are directed.By employing adequate beam dumps matched to beam-divergence, magnets, passive shielding and laser pulse repetition limits, average dose rates in- and outside the experimental building stay below design specifications (<0.5µSv h-1) for unclassified areas,<2.5µSv h-1for supervised areas,<7.5µSv h-1maximum local dose rate) and regulatory limits (<1mSv a-1for unclassified areas).

A feasibility study of zebrafish embryo irradiation with laser-accelerated protons.

The development from single shot basic laser plasma interaction research toward experiments in which repetition rated laser-driven ion sources can be applied requires technological improvements. For example, in the case of radio-biological experiments, irradiation duration and reproducible controlled conditions are important for performing studies with a large number of samples. We present important technological advancements of recent years at the ATLAS 300 laser in Garching near Munich since our last radiation biology experiment. Improvements range from target positioning over proton transport and diagnostics to specimen handling. Exemplarily, we show the current capabilities by performing an application oriented experiment employing the zebrafish embryo model as a living vertebrate organism for laser-driven proton irradiation. The size, intensity, and energy of the laser-driven proton bunches resulted in evaluable partial body changes in the small (<1 mm) embryos, confirming the feasibility of the experimental system. The outcomes of this first study show both the appropriateness of the current capabilities and the required improvements of our laser-driven proton source for in vivo biological experiments, in particular the need for accurate, spatially resolved single bunch dosimetry and image guidance.

Optimization and performance study of a proton CT system for pre-clinical small animal imaging.

Proton computed tomography (pCT) promises to reduce or even eliminate range uncertainties inherent in the conversion of Hounsfield units into relative stopping power (RSP) for proton therapy treatment planning. This is of particular interest for proton irradiation studies in animal models due to the high precision required and uncertainties in tissue properties. We propose a dedicated single-particle tracking pCT system consisting of low material budget floating strip Micromegas detectors for tracking and a segmented time-projection-chamber with vertical Mylar absorbers, functioning as a range telescope. Based on Monte Carlo simulations of a realistic in silico beam and detector implementation, a geometrical optimization of the system components was conducted to safeguard an ideal operation close to intrinsic performance limits at 75 MeV. Moreover, the overall imaging capabilities relevant for pre-clinical proton therapy treatment planning were evaluated for a mouse model. In order to minimize extrinsic uncertainties in the estimated proton trajectories, a spacing of the two tracking planes of at least 7 cm is required in both tracking detectors. Additionally, novel in-house developed and produced aluminum-based readout electrodes promise superior performance with around 3 mm-1 spatial resolution due to the reduced material budget. Concerning the range telescope, an absorber thickness within 500 µm to 750 µm was found to yield the best compromise between water-equivalent path length resolution and complexity of the detector instrumentation, still providing sub-0.5% RSP accuracy. The optimized detector configuration enables better than 2% range accuracy for proton therapy treatment planning in pre-clinical data sets. This work outlines the potential of pCT for small animal imaging. The performance of the proposed and optimized system provides superior treatment planning accuracy compared to conventional x-ray CT. Thus, pCT can play an important role in translational and pre-clinical cancer research.

A phenotypic screening platform utilising human spermatozoa identifies compounds with contraceptive activity.

There is an urgent need to develop new methods for male contraception, however a major barrier to drug discovery has been the lack of validated targets and the absence of an effective high-throughput phenotypic screening system. To address this deficit, we developed a fully-automated robotic screening platform that provided quantitative evaluation of compound activity against two key attributes of human sperm function: motility and acrosome reaction. In order to accelerate contraceptive development, we screened the comprehensive collection of 12,000 molecules that make up the ReFRAME repurposing library, comprising nearly all the small molecules that have been approved or have undergone clinical development, or have significant preclinical profiling. We identified several compounds that potently inhibit motility representing either novel drug candidates or routes to target identification. This platform will now allow for major drug discovery programmes that address the critical gap in the contraceptive portfolio as well as uncover novel human sperm biology.

Degradation of emerging organic pollutants in wastewater effluents by electrochemical photocatalysis on nanostructured TiO2 meshes.

An immobilized photoactive TiO2 coating grown directly on titanium meshes was successfully exploited for the electrochemical photocatalytic degradation of carbamazepine in real secondary wastewater effluent. The catalyst was prepared by Plasma Electrolytic Oxidation and during the photocatalytic water treatment an electrical polarization (bias) was applied to the catalyst. The investigated process was compared with the conventional one employing suspended TiO2 powder (Degussa P25). Results showed that carbamazepine degradation rate follows the order UV/supported TiO2+bias ≈ UV/TiO2 Degussa P25 > UV/supported TiO2 > UV. The investigation also included the identification of other micropollutants and degradation products. This allowed the detection of 201 compounds present in the secondary wastewater effluent employed for the photocatalysis tests, 51 of them also successfully associated to compounds of emerging concern (CECs), and 194 to transformation products (TPs). The degradation of detected compounds followed first-order kinetics and the mean kinetic constant values of the 51 CECs resulted to be 0.048, 0.035 and 0.043 min-1 for the TiO2+Bias + UV, TiO2+UV and UV, respectively. As for TPs, results showed that the TiO2+Bias + UV treatment is much more efficient than both TiO2+UV and UV in minimizing the intensity of the organics in the real wastewater. Such a better performance was more pronounced at higher reaction time reaching 60% reduction of mean peak area of TPs at 90 min of reaction. Among the detected TPs also compounds belonging to known carbamazepine TPs were found. This allowed to propose a degradation pathway of carbamazepine. The supported catalyst was positively tested for 15 cycles demonstrating that it has the potential to be used in real wastewater tertiary steps aimed at removing CECs.

I-BEAT: Ultrasonic method for online measurement of the energy distribution of a single ion bunch.

The shape of a wave carries all information about the spatial and temporal structure of its source, given that the medium and its properties are known. Most modern imaging methods seek to utilize this nature of waves originating from Huygens' principle. We discuss the retrieval of the complete kinetic energy distribution from the acoustic trace that is recorded when a short ion bunch deposits its energy in water. This novel method, which we refer to as Ion-Bunch Energy Acoustic Tracing (I-BEAT), is a refinement of the ionoacoustic approach. With its capability of completely monitoring a single, focused proton bunch with prompt readout and high repetition rate, I-BEAT is a promising approach to meet future requirements of experiments and applications in the field of laser-based ion acceleration. We demonstrate its functionality at two laser-driven ion sources for quantitative online determination of the kinetic energy distribution in the focus of single proton bunches.