Hard X-ray phase tomography for brain tissue imaging

Phase tomography based on hard X-ray double-grating interferometry (XDGI) is a well-established imaging technique for the three-dimensional visualization of soft tissues, providing tomograms with superior contrast. The experimental setup contains a beam-splitter grating and an analyzer grating. Both gratings have to be placed and oriented with high precision for an optimized functioning of the interferometer. The analyzer grating can be omitted, if the detection unit allows a direct detection of the interference pattern. Such a setup is termed hard X-ray single-grating interferometer (XSGI). XSGI profits from easier handling, as only one grating needs to be aligned, and from the related cost reduction. But, more importantly than that, for the XSGI the spatial resolution is not limited by the period of the analyzer grating, and for equal photon flux, the number of detected photons is increased by a factor of about two. In the present thesis, a peripheral human nerve was embedded in paraffin. In order to compare the performance of XSGI and XDGI for medically relevant, low-absorbing specimens, for both modalities the specimen was measured at the facility Deutsches Elektronen-Synchrotron (DESY), using synchrotron radiation. Subsequently, the acquired tomograms were superimposed using rigid registration, i.e. one dataset was translated and rotated to best fit the other one. Both techniques allow resolving anatomical features of the nerve investigated, including epineurium, perineurium, and endoneurium. Whereas the XDGI data exhibit a better contrast-to-noise ratio, the XSGI tomogram shows an improved spatial resolution by a factor close to two. Thus, it can be concluded that XSGI is the preferred approach for the visualization of paraffin-embedded soft tissues

Implementation of a novel nursing assessment tool in geriatric trauma patients with proximal femur fractures

BACKGROUND Geriatric trauma patients represent a special challenge in postoperative care and are prone to specific complications. The goal of this study was to analyse the predictive potential of a novel nursing assessment tool, the outcome-oriented nursing assessment for acute care (ePA-AC), in geriatric trauma patients with proximal femur fractures (PFF). METHODS A retrospective cohort study of geriatric trauma patients aged ≥ 70 years with PFF was conducted at a level 1 trauma centre. The ePA-AC is a routinely used tool that evaluates pneumonia; confusion, delirium and dementia (CDD); decubitus (Braden Score); the risk of falls; the Fried Frailty index (FFI); and nutrition. Assessment of the novel tool included analysis of its ability to predict complications including delirium, pneumonia and decubitus. RESULTS The novel ePA-AC tool was investigated in 71 geriatric trauma patients. In total, 49 patients (67.7%) developed at least one complication. The most common complication was delirium (n = 22, 44.9%). The group with complications (Group C) had a significantly higher FFI compared with the group without complications (Group NC) (1.7 ± 0.5 vs 1.2 ± 0.4, p = 0.002). Group C had a significantly higher risk score for malnutrition compared with Group NC (6.3 ± 3.4 vs 3.9 ± 2.8, p = 0.004). A higher FFI score increased the risk of developing complications (odds ratio [OR] 9.8, 95% confidence interval [CI] 2.0 to 47.7, p = 0.005). A higher CDD score increased the risk of developing delirium (OR 9.3, 95% CI 2.9 to 29.4, p < 0.001). CONCLUSION The FFI, CDD, and nutritional assessment tools are associated with the development of complications in geriatric trauma patients with PFF. These tools can support the identification of geriatric patients at risk and might guide individualised treatment strategies and preventive measures

Sono-Electro-Magnetic Therapy for Treating Chronic Pelvic Pain Syndrome in Men: A Randomized, Placebo-Controlled, Double-Blind Trial.

OBJECTIVE To assess the efficacy and safety of sono-electro-magnetic therapy compared to placebo in men with refractory CPPS. PATIENTS AND METHODS In a randomized, placebo-controlled, double-blind single center trial, we assessed the effect of sono-electro-magnetic therapy in men with treatment refractory CPPS. Sixty male patients were randomly assigned to treatment with either sono-electro-magnetic (n = 30) or placebo therapy (n = 30) for 12 weeks. The primary outcome was a change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) from baseline to 12 weeks. RESULTS The 12-week difference between sono-electro-magnetic and placebo therapy in changes of the NIH-CPSI total score was -3.1 points (95% CI -6.8 to 0.6, p = 0.11). In secondary comparisons of NIH-CPSI sub-scores, we found differences between groups most pronounced for the quality-of-life sub-score (difference at 12 weeks -1.6, 95% CI -2.8 to -0.4, p = 0.015). In stratified analyses, the benefit of sono-electro-magnetic therapy appeared more pronounced among patients who had a symptom duration of 12 months or less (difference in NIH-CPSI total score -8.3, 95% CI -14.5 to 2.6) than in patients with a longer symptom duration (-0.8, 95% CI -4.6 to 3.1; p for interaction = 0.023). CONCLUSIONS Sono-electro-magnetic therapy did not result in a significant improvement of symptoms in the overall cohort of treatment refractory CPPS patients compared to placebo treatment. Subgroup analysis indicates, however, that patients with a symptom-duration of 12 months or less may benefit from sono-electro-magnetic therapy, warranting larger randomized controlled trials in this subpopulation. TRIAL REGISTRATION ClinicalTrials.gov NCT00688506

Supraphysiologic Testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions

Since Huggins defined the androgen-sensitive nature of prostate cancer (PCa), suppression of systemic testosterone (T) has remained the most effective initial therapy for advanced disease although progression inevitably occurs. From the inception of clinical efforts to suppress androgen receptor (AR) signaling by reducing AR ligands, it was also recognized that administration of T in men with castration-resistant prostate cancer (CRPC) could result in substantial clinical responses. Data from preclinical models have reproducibly shown biphasic responses to T administration, with proliferation at low androgen concentrations and growth inhibition at supraphysiological T concentrations. Many questions regarding the biphasic response of PCa to androgen treatment remain, primarily regarding the mechanisms driving these responses and how best to exploit the biphasic phenomenon clinically. Here we review the preclinical and clinical data on high dose androgen growth repression and discuss cellular pathways and mechanisms likely to be involved in mediating this response. Although meaningful clinical responses have now been observed in men with PCa treated with high dose T, not all men respond, leading to questions regarding which tumor characteristics promote response or resistance, and highlighting the need for studies designed to determine the molecular mechanism(s) driving these responses and identify predictive biomarkers

Genetic Signatures of a Demographic Collapse in a Large-Bodied Forest Dwelling Primate (Mandrillus Leucophaeus)

It is difficult to predict how current climate change will affect wildlife species adapted to a tropical rainforest environment. Understanding how population dynamics fluctuated in such species throughout periods of past climatic change can provide insight into this issue. The drill (Mandrillus leucophaeus) is a large-bodied rainforest adapted mammal found in West Central Africa. In the middle of this endangered monkey’s geographic range is Lake Barombi Mbo, which has a well-documented palynological record of environmental change that dates to the Late Pleistocene. We used a Bayesian coalescent-based framework to analyze 2,076 base pairs of mitochondrial DNA across wild drill populations to infer past changes in female effective population size since the Late Pleistocene. Our results suggest that the drill underwent a nearly 15-fold demographic collapse in female effective population size that was most prominent during the Mid Holocene (approximately 3-5 Ka). This time period coincides with a period of increased dryness and seasonality across Africa and a dramatic reduction in forest coverage at Lake Barombi Mbo.We believe that these changes in climate and forest coverage were the driving forces behind the drill population decline. Furthermore, the warm temperatures and increased aridity of the Mid Holocene are potentially analogous to current and future conditions faced by many tropical rainforest communities. In order to prevent future declines in population size in rainforest-adapted species such as the drill, large tracts of forest should be protected to both preserve habitat and prevent forest loss through aridification. 55

Understanding meta-population trends of the Australian fur seal, with insights for adaptive monitoring

Effective ecosystem-based management requires estimates of abundance and population trends of species of interest. Trend analyses are often limited due to sparse or short-term abundance estimates for populations that can be logistically difficult to monitor over time. Therefore it is critical to assess regularly the quality of the metrics in long-term monitoring programs. For a monitoring program to provide meaningful data and remain relevant, it needs to incorporate technological improvements and the changing requirements of stakeholders, while maintaining the integrity of the data. In this paper we critically examine the monitoring program for the Australian fur seal (AFS) Arctocephalus pusillus doriferus as an example of an ad-hoc monitoring program that was co-ordinated across multiple stakeholders as a range-wide census of live pups in the Austral summers of 2002, 2007 and 2013. This 5-yearly census, combined with historic counts at individual sites, successfully tracked increasing population trends as signs of population recovery up to 2007. The 2013 census identified the first reduction in AFS pup numbers (14,248 live pups, -4.2% change per annum since 2007), however we have limited information to understand this change. We analyse the trends at breeding colonies and perform a power analysis to critically examine the reliability of those trends. We then assess the gaps in the monitoring program and discuss how we may transition this surveillance style program to an adaptive monitoring program than can evolve over time and achieve its goals. The census results are used for ecosystem-based modelling for fisheries management and emergency response planning. The ultimate goal for this program is to obtain the data we need with minimal cost, effort and impact on the fur seals. In conclusion we identify the importance of power analyses for interpreting trends, the value of regularly assessing long-term monitoring programs and proper design so that adaptive monitoring principles can be applied

Patient-derived xenografts and organoids model therapy response in prostate cancer.

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds