Advanced portable micro-SORS prototype coupled with SERDS for heritage science.

We investigate the subsurface composition of turbid materials at the micro scale by means of a portable non-invasive technique, micro-spatially offset Raman spectroscopy (micro-SORS), combined with shifted excitation Raman difference spectroscopy (SERDS). This combination enables the microscale layer analysis and allows to deal effectively with highly fluorescing samples as well as ambient light, all in a form of an in-house portable prototype device optimised for applications in heritage science. The instrument comprises ability to simultaneously collect multiple spectra by means of an optical fibre bundle, thus reducing the dead time and simplifying the ease of deployment of the technique. The performance of the synergy between micro-SORS and 785 nm SERDS dual-wavelength diode laser is demonstrated on a stratified mock-up painting samples including highly fluorescing painted layers. This instrumental approach could be ground-breaking in heritage science, due to the largely unmet need of analysing the molecular composition of subsurface of artworks non-invasively and in situ, and in the presence of fluorescent background and ambient light. Moreover, many other fields are expected to benefit from this technological advancement such as solar energy, forensic and food analytical areas.

Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo-controlled N-of-1 trials.

BACKGROUND: Many rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design. METHODS: We aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants' natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across disorders combining data from the individual N-of-1 trials. DISCUSSION: These N-of-1 trials address an unmet medical need and will provide information on the effectiveness of CBD for severe behavioral manifestations in RGNDs, potentially generating generalizable knowledge at an individual-, disorder- and RGND population level. TRIAL REGISTRATION: EudraCT: 2021-003250-23, registered 25 August 2022, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-003250-23/NL .

Ambient Hydrocarbon Detection with an Ultra-Low-Loss Cavity Raman Analyzer.

The detection of ambient outdoor trace hydrocarbons was investigated with a multipass Raman analyzer. It relies on a multimode blue laser diode receiving optical feedback from a retroreflecting multipass optical cavity, effectively creating an external cavity diode laser within which spontaneous Raman scattering enhancement occurs. When implemented with ultra-low-loss mirrors, a more than 20-fold increase in signal-to-background ratio was obtained, enabling proximity detection of trace motor vehicle exhaust gases such as H2, CO, NO, CH4, C2H2, C2H4, and C2H6. In a 10-min-long measurement at double atmospheric pressure, the limits of detection obtained were near or below 100 ppb for most analytes.

Vibrationally Resolved Inner-Shell Photoexcitation of the Molecular Anion C2.

Carbon 1s core-hole excitation of the molecular anion C2 - has been experimentally studied at high resolution by employing the photon-ion merged-beams technique at a synchrotron light source. The experimental cross section for photo-double-detachment shows a pronounced vibrational structure associated with 1 σ u → 3 σ g ${1\sigma _u \to 3\sigma _g }$ and 1 σ g → 1 π u ${1\sigma _g \to 1\pi _u }$ core excitations of the C2 - ground level and first excited level, respectively. A detailed Franck-Condon analysis reveals a strong contraction of the C2 - molecular anion by 0.2 Šupon this core photoexcitation. The associated change of the molecule's moment of inertia leads to a noticeable rotational broadening of the observed vibrational spectral features. This broadening is accounted for in the present analysis which provides the spectroscopic parameters of the C2 - 1 σ u - 1 3 σ g 2 2 Σ u + ${1\sigma _u^{ - 1} \,3\sigma _g^2 \;^2 \Sigma _u^ + }$ and 1 σ g - 1 3 σ g 2 2 Σ g + ${1\sigma _g^{ - 1} \,3\sigma _g^2 \;^2 \Sigma _g^ + }$ core-excited levels.

Therapy satisfaction and health literacy are key factors to improve medication adherence in systemic sclerosis.

OBJECTIVE: Although medication adherence (MA) contributes to therapeutic outcome in systemic sclerosis (SSc), research data are scarce. Factors influencing MA in SSc are hardly known. METHOD: We conducted a monocentric, cross-sectional study on 85 patients with SSc at the University of Lübeck, Germany, using the Compliance Questionnaire of Rheumatology as the main measurement tool of MA. We also used the Scleroderma Health Assessment Questionnaire, Illness Perception Questionnaire - Revised, Health Literacy Questionnaire, Lübeck Medication Satisfaction Questionnaire (a novel instrument created for this study), and patients' demographic and clinical data, to find factors contributing to MA. RESULTS: Good MA was seen in 51.8% of patients. MA was positively associated with therapy satisfaction (p < 0.001), modified Rodnan Skin Score (p = 0.032), age (p = 0.025), intake of micronutrients (p = 0.033), number of prescribed drugs (p = 0.014), and some dimensions of health literacy. Negative associations were found for patients with weight loss attributed to SSc (p = 0.009) and the perception that the disease is caused by the patient's personality (p = 0.011) or emotional state (p = 0.037). CONCLUSION: Although most SSc patients display good MA, non-adherence remains a major problem. Patients should be assessed for non-adherence. The factors affecting MA identified herein could help to improve therapeutic outcomes.

Nitrofurantoin for the treatment of uncomplicated urinary tract infection in female patients: the impact of dosing regimen, age, and renal function on drug exposure.

PURPOSE: The aim of this study is to determine nitrofurantoin exposure in female patients with different age and renal function with complaints of an uncomplicated UTI. Also the nitrofurantoin exposure in relation to the dosage regimen will be studied. METHODS: Eight general practitioners (GP) participated in the study and included 38 patients with symptoms of an uncomplicated UTI, treated either with a dose of 50 mg q6h or 100 mg q12h, upon the discretion of the GP. Nitrofurantoin exposure was quantified in the patient's 24-h urine samples by UHPLC-UV and the area under the curve was calculated. RESULTS: The 38 patients provided a range of 2-17 urine samples. The urine nitrofurantoin exposure was 1028 mg h/L for the patients receiving 50 mg q6h and 1036 mg h/L for those treated with 100 mg q12h (p = 0.97) and was not affected by age and eGFR (p = 0.64 and p = 0.34, respectively). CONCLUSION: The data obtained do not support the discouragement of nitrofurantoin use in the elderly and in patients with impaired renal function. Since only a small number of patients were included, a larger study with more patients is warranted to evaluate nitrofurantoin exposure and adverse effects.

Does REACH provide sufficient information to regulate substances toxic to reproduction?

Hazard classification and risk assessment of substances, is essential to protect workers and consumers from hazardous substances including reproductive toxicants. The ability to classify substances for reproductive toxicity under the current REACH information requirements has been assessed. For low tonnage substances (<10 ton per annum (tpa)) information for classification is insufficient. When only a reproductive screening study is available (10-100 tpa), substances are mostly not classified in Category 1B as developmental and non-potent fertility effects may be missed. The information requirements could be improved by automatic triggering of follow-up studies in case of a Category 2 classification based on a screening study. Additionally, a study could be added to the information requirements for substances produced at 1-10 tpa. Performing a risk assessment is often problematic due to the limited study requirements at low tonnage levels. Only for substances produced at more than 100 tpa, there is a high likelihood to detect reproductive effects and perform accurate risk assessment provided that the extended-one-generation-reproductive-toxicity-study and/or extra cohorts are triggered where required. Regardless of the tonnage level, no specific studies on lactation are required. With this paper we intend to contribute to the discussion on the information requirements for reproductive toxicity in view of the REACH revision.

Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial.

BACKGROUND: The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase III trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS: A clinical-grade whole-transcriptome assay was carried out on radical prostatectomy samples obtained from patients enrolled in Swiss Group for Clinical Cancer Research (SAKK) 09/10, a phase III trial of 350 men with biochemical recurrence after radical prostatectomy randomized to 64 Gy versus 70 Gy without concurrent hormonal therapy or pelvic nodal RT. A prespecified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, postradical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS: The analytic cohort of 226 patients was representative of the overall trial, with a median follow-up of 6.3 years (interquartile range 6.1-7.2 years). The GC (high versus low-intermediate) was independently associated with biochemical progression [subdistribution hazard ratio (sHR) 2.26, 95% confidence interval (CI) 1.42-3.60; P < 0.001], clinical progression (HR 2.29, 95% CI 1.32-3.98; P = 0.003), and use of hormone therapy (sHR 2.99, 95% CI 1.55-5.76; P = 0.001). GC high patients had a 5-year freedom from biochemical progression of 45% versus 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower versus higher GC scores. CONCLUSIONS: This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. These data confirm the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting.

Assessing feasibility, construct validity, and reliability of a new aged care-specific preference-based quality of life instrument: evidence from older Australians in residential aged care.

BACKGROUND: Quality of Life-Aged Care Consumers (QOL-ACC) is a new older-person-specific quality of life instrument designed for application in quality assessment and economic evaluation in aged care. The QOL-ACC was designed from its inception with older people receiving aged care services ensuring its strong content validity. Given that the QOL-ACC has already been validated in home care settings and a preference-weighted value set developed, we aimed to assess feasibility, construct validity and reliability of the QOL-ACC in residential aged care settings.  METHODS: Individuals living in residential aged care facilities participated in an interviewer-facilitated survey. The survey included the QOL-ACC, QCE-ACC (quality of aged care experience measure) and two other preference-based quality of life instruments (ASCOT and EQ-5D-5L). Feasibility was assessed using missing data and ceiling/floor effects. Construct validity was assessed by exploring the relationship between the QOL-ACC and other instruments (convergent validity) and the QOL-ACC's ability to discriminate varying levels of self-rated health and quality of life. Internal consistency reliability was assessed using Cronbach's alpha (α). RESULTS: Of the 200 residents (mean age, 85 ± 7.7 years) who completed the survey, 60% were female and 69% were born in Australia. One in three participating residents self-rated their health as fair/poor. The QOL-ACC had no missing data but had small floor effects (0.5%) and acceptable ceiling effects (7.5%). It demonstrated moderate correlation with ASCOT (r = 0.51, p < 0.001) and EQ-5D-5L (r = 0.52, p < 0.001) and a stronger correlation with the QCE-ACC (r = 0.57, p < 0.001). Residents with poor self-rated health and quality of life had significantly lower scores on the QOL-ACC. The internal consistency reliability of the QOL-ACC and its dimensions was good (α = 0.70-0.77). CONCLUSIONS: The QOL-ACC demonstrated good feasibility, construct validity and internal consistency reliability to assess aged care-related quality of life. Moderate correlations of the QOL-ACC and other instruments provide evidence of its construct validity and signifies that the QOL-ACC adds non-redundant and non-interchangeable information beyond the existing instruments. A stronger correlation with the QCE-ACC than other instruments may indicate that quality of life is more intimately connected with the care experience than either health- or social-related quality of life in residential aged care settings.

Prescription opioids among older adults: ten years of data across five countries.

BACKGROUND: Opioid use has increased globally in the recent decade. Although pain remains a significant problem among older adults, susceptibility to opioid-related harms highlights the importance of careful opioid therapy monitoring on individual and societal levels. We aimed to describe the trends of prescription opioid utilisation among residents aged ≥65 in all Nordic countries during 2009-2018. METHODS: We conducted cross-sectional measurements of opioid utilisation in 2009-2018 from nationwide registers of dispensed drugs in Denmark, Finland, Iceland, Norway, and Sweden. The measures included annual opioid prevalence, defined daily doses (DDDs) per 1000 inhabitants per day (DIDs), and morphine milligram equivalents (MMEs) per user per day. RESULTS: From 2009 to 2018, an average of 808,584 of adults aged ≥65 used opioids yearly in all five countries; an average annual prevalence of 17.0%. During this time period, the prevalence decreased in Denmark, Norway, and Sweden due to declining codeine and/or tramadol use. Iceland had the highest opioid prevalence in 2009 (30.2%), increasing to 31.7% in 2018. In the same period, DIDs decreased in all five countries, and ranged from 28.3 in Finland to 58.5 in Denmark in 2009, and from 23.0 in Finland to 54.6 in Iceland in 2018. MMEs/user/day ranged from 4.4 in Iceland to 19.6 in Denmark in 2009, and from 4.6 in Iceland to 18.8 in Denmark in 2018. In Finland, Norway, and Sweden, MMEs/user/day increased from 2009 to 2018, mainly due to increasing oxycodone utilisation. CONCLUSIONS: The stable or decreasing opioid utilisation prevalence among a majority of older adults across the Nordic countries coincides with an increase in treatment intensity in 2009-2018. We found large cross-national differences despite similarities across the countries' cultures and healthcare systems. For the aged population, national efforts should be placed on improving pain management and monitoring future trends of especially oxycodone utilisation.

The arthroscopic Bankart operation: a 10-year follow-up study.

INTRODUCTION: Traumatic shoulder instability most frequently occurs in young people often during sports events. Currently, the arthroscopic Bankart repair is the therapy of choice in the absence of extensive glenoid bone loss and has proved to be a safe and effective procedure. Nevertheless, we see recurrence of instability-especially if new trauma happens-and further data are needed to guide the right decision-making for these often young patients. The purpose of this study was to determine the long-term outcome 10 years after arthroscopic Bankart operation in terms of satisfaction of the patient, functional result, complications, recurrent instability, and development of osteoarthritis, and to look after possible risk factors for recurrence of instability and statistical proof of these. MATERIALS AND METHODS: Thirty-nine out of 49 patients underwent physical examination of both shoulders. We could perform a postoperative shoulder a-p X-ray in 28 patients. According to Samilson, [24] the extent of osteoarthritis was measured. The Constant score and the postoperative ROWE score were determined for both shoulders as well as the WOSI Score. In 25 cases, we calculated the ISIS Score. RESULTS: We could reach out to 89.6% of patients and 79.6% could be physically examined. The vast majority of 95.5% are either very satisfied or satisfied with the result at the time we ended the follow-up. The mean Constant score of 95.5 reflects this result. In contrast to this, we found at the same time in 15.3% ongoing clinical signs of instability of the concerning shoulder, even though 9.1% had to be re-operated for recurrent instability in between the follow-up timeline and we found in the X-rays (57.1% of all patients) in 35.7% at least moderate and in 10.7% severe signs of osteoarthritis. The Constant score but not the ROWE score differed significantly in patients with no or mild compared to those with moderate-to-severe osteoarthritis. CONCLUSIONS: The arthroscopic Bankart stabilization procedure showed after 10 years to be a very safe operation and to be able to produce a satisfying and functional very good long-term result-reflected by the Constant score. We assume that the extent of osteoarthritis seems to be the determining factor of the very good functional result, even though ongoing instability was present in 15.3% of the patients.

Brainstem Dysfunction in Healthy Aging.

The brainstem controls sub-cortical and cortical activity and influences the processing of incoming information. The goal of this study was to characterize age related alterations of brainstem-brain interactions during different brain states detected by dynamic analysis of task-free fMRI. 79 young (20-40 years) and 51 older adults (55-80 years) were studied. Internal brainstem structures were segmented using a new multi-contrast segmentation approach. Brain and brainstem gray matter segmentations were warped onto a population template. The ICV-corrected Jacobian determinants were converted into z-score maps and the means from 420 cortical/subcortical/brainstem rois extracted. The fMRI was preprocessed in SPM12/Conn18 and the BOLD signal from 420 cortical/subcortical/brainstem rois extracted. A dynamic task-free analysis approach based on hierarchical cluster analysis was used to identify 15 brain states that were characterized using graph analysis (strength, diversity, modularity). Kruskal-Wallis tests and Spearman correlations were used for statistical analysis. One brain state (cluster 21) occurred more often in older adults (p=0.008). It was characterized by a lower mean modular strength and brainstem-cortical strength in older adults compared to younger adults. Global age related gray matter differences were positively correlated with brain state 21's modular strength. Furthermore, brain state 21 duration was negatively correlated with working memory (r = -0.28, p=0.002). The findings suggest an age related weakening of the within and between network synchronization at the brainstem level during brain state 21 in older adults that negatively affects cortical and subcortical synchronization and working memory performance.

Revisiting Polymer-Particle Interaction in PEO Solutions.

We have measured the electrophoretic mobility and diffusion coefficient of carboxylate-modified and sulfate-modified polystyrene latex particles in poly(ethylene oxide) aqueous solutions. Carboxylate-modified polystyrene particles have shown a bound polymeric layer as the surface net charge vanishes even at very low poly(ethylene oxide) concentration. The polymeric layer causes a lower electrophoretic mobility and slower Brownian diffusion than that corresponding to the bare particles. We show that the diffusion is the result of a significantly increased effective particle size 2rheff = 30 nm. This bound layer is not present in sulfate-modified polystyrene latex particles. The interaction between the carboxylate-modified particle surface and the macromolecules has been confirmed by means of atomistic computer simulations. The grafted acrylate copolymers, which come from the preparation procedure of the latex particles, confer more hydrophobic surface ready to interact with the polymer. The simulations suggest that the interaction is modulated not only by the nature of the acrylic acid monomer but also by the length of the grafted copolymer. Our results have important implications for particle selection in microrheology experiments.

Brain/blood ratios of methadone and ABCB1 polymorphisms in methadone-related deaths.

Methadone is an opioid that often leads to fatalities. Interpretation of toxicological findings can be challenging if no further information about the case history is available. The aims of this study were (1) to determine whether brain/blood ratios can assist in the interpretation of methadone findings in fatalities; (2) to examine whether polymorphisms in the gene encoding the P-glycoprotein (also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1)), which functions as a multispecific efflux pump in the blood-brain barrier, affect brain/blood ratios of methadone. Femoral venous blood and brain tissue (medulla oblongata and cerebellum) from 107 methadone-related deaths were analysed for methadone by gas chromatography-mass spectrometry. In addition, all the samples were genotyped for three common ABCB1 single nucleotide polymorphisms (SNPs rs1045642, rs1128503, and rs2032582) using ion-pair reversed-phase high-performance liquid chromatography-electrospray ionization mass spectrometry (ICEMS). In nearly all cases, methadone concentrations were higher in the brain than in the blood. Inter-individual brain/blood ratios varied (0.6-11.6); the mean ratio was 2.85 (standard deviation 1.83, median 2.35). Moreover, significant differences in mean brain/blood ratios were detected among the synonymous genotypes of rs1045642 in ABCB1 (p = 0.001). Cases with the T/T genotype had significantly higher brain/blood ratios than cases with the other genotypes (T/T vs. T/C difference (d) = 1.54, 95% CI [1.14, 2.05], p = 0.002; T/T vs. C/C d = 1.60, 95% CI [1.13, 2.29], p = 0.004). Our results suggest that the rs1045642 polymorphisms in ABCB1 may affect methadone concentrations in the brain and its site of action and may be an additional factor influencing methadone toxicity.

Aspect ratio of nano/microstructures determines Staphylococcus aureus adhesion on PET and titanium surfaces.

AIMS: Joint infections cause premature implant failure. The avoidance of bacterial colonization of implant materials by modification of the material surface is therefore the focus of current research. In this in vitro study the complex interaction of periodic structures on PET and titanium surfaces on the adhesion of Staphylococcus aureus is analysed. METHODS AND RESULTS: Using direct laser interference patterning as well as roll-to-roll hot embossing methods, structured periodic textures of different spatial distance were produced on surfaces and S. aureus were cultured for 24 h on these. The amount of adhering bacteria was quantified using fluorescence microscopy and the local adhesion behaviour was investigated using scanning electron microscopy. For PET structures, minimal bacterial adhesion was identified for an aspect ratio of about 0·02. On titanium structures, S. aureus adhesion was significantly decreased for profile heights of < 200 nm. Our results show a significantly decreased bacterial adhesion for structures with an aspect ratio range of 0·02 to 0·05. CONCLUSIONS: We show that structuring on surfaces can decrease the amount of S. aureus on titanium and PET as common implant materials. SIGNIFICANCE AND IMPACT OF THE STUDY: The study highlights the immense potential of applying specific structures to implant materials to prevent implant colonization with pathogen bacteria.

Role of the community pharmacist in detecting frailty and spatio-temporal disorientation among community-dwelling older people in France.

BACKGROUND: Many older community-dwelling subjects may be frail and/or disoriented, putting them at risk of adverse outcomes. We investigated the prevalence of frailty and spatiotemporal disorientation among patients aged > 65 years collecting regular medication at a community pharmacy. METHODS: Prospective, cross-sectional study of geriatric evaluation in 218 community pharmacies in France. Regular customers aged > 65 years attending the pharmacy to receive ≥ 1 prescription drug were eligible. Spatio-temporal disorientation was assessed using a 4-item screening test; subjects were considered disoriented if they had ≥ 1 incorrect answers. Frailty was evaluated using the Short Emergency Geriatric Assessment (SEGA) grid. Subjects were considered as not frail (score < 8), or frail/very frail (score of 8 or more). RESULTS: 4090 subjects were included, average age 77.5 ± 7.6 years, 60.1% females. Overall, 1025 (25%) were frail/very frail, and 384 (9.4%) were disoriented in space or time. On average, subjects were taking 5.4 ± 3.5 medications per day. Among non-frail patients, 116/3065 (3.8%) were disoriented, of whom 87 (87/116, 75%) managed their medication alone. Among frail/very frail patients, 268/1025 (26.1%) were disoriented, of whom 46 (46/268, 16.8%) managed their medication alone. The majority of patients (77.9%) collected their medication alone at the pharmacy, but significantly fewer frail patients came to collect their drugs alone (p < 0.001). CONCLUSION: It is feasible for community pharmacists to detect disorientation and frailty among older patients. A quarter of subjects were frail/very frail, and 3.2% were disoriented yet managing their drugs alone. Additional social support should be envisaged for these subjects.

CCL20-CCR6 axis directs sperm-oocyte interaction and its dysregulation correlates/associates with male infertility‡.

The interaction of sperm with the oocyte is pivotal during the process of mammalian fertilization. The limited numbers of sperm that reach the fallopian tube as well as anatomic restrictions indicate that human sperm-oocyte encounter is not a matter of chance but a directed process. Chemotaxis is the proposed mechanism for re-orientating sperm toward the source of a chemoattractant and hence to the oocyte. Chemokines represent a superfamily of small (8-11 kDa), cytokine-like proteins that have been shown to mediate chemotaxis and tissue-specific homing of leukocytes through binding to specific chemokine receptors such as CCRs. Here we show that CCR6 is abundantly expressed on human sperms and in human testes. Furthermore, radioligand-binding experiments showed that CCL20 bound human sperm in a specific manner. Conversely, granulosa cells of the oocyte-surrounding cumulus complex as well as human oocytes represent an abundant source of the CCR6-specific ligand CCL20. In human ovaries, CCL20 shows a cycle-dependent expression pattern with peak expression in the preovulatory phase and CCL20 protein induces chemotactic responses of human sperm. Neutralization of CCL20 in ovarian follicular fluid significantly impairs sperm migratory responses. Conversely, analyses in infertile men with inflammatory conditions of the reproductive organs demonstrate a significant increase of CCL20/CCR6 expression in testis and ejaculate. Taken together, findings of the present study suggest that CCR6-CCL20 interaction may represent an important factor in directing sperm-oocyte interaction.

Multiple Photodetachment of Carbon Anions via Single and Double Core-Hole Creation.

We report on new measurements of m-fold photodetachment (m=2-5) of carbon anions via K-shell excitation and ionization. The experiments were carried out employing the photon-ion merged-beams technique at a synchrotron light source. While previous measurements were restricted to double detachment (m=2) and to just the lowest-energy K-shell resonance at about 282 eV, our absolute experimental m-fold detachment cross sections at photon energies of up to 1000 eV exhibit a wealth of new thresholds and resonances. We tentatively identify these features with the aid of detailed atomic-structure calculations. In particular, we find unambiguous evidence for fivefold detachment via double K-hole production.

Influence of localization of PSMA-positive oligo-metastases on efficacy of metastasis-directed external-beam radiotherapy-a multicenter retrospective study.

PURPOSE: Approximately 40-70% of biochemically persistent or recurrent prostate cancer (PCa) patients after radical prostatectomy (RPE) are oligo-metastatic in 68gallium-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET). Those lesions are frequently located outside the prostate bed, and therefore not cured by the current standards of care like external-beam radiotherapy (EBRT) of the prostatic fossa. This retrospective study analyzes the influence of oligo-metastases' site on outcome after metastasis-directed radiotherapy (MDR). METHODS: Retrospectively, 359 patients with PET-positive PCa recurrences after RPE were analyzed. Biochemical recurrence-free survival (BRFS) (prostate-specific antigen (PSA) < post-radiotherapy nadir + 0.2 ng/mL) was assessed using Kaplan-Meier survival and Cox regression analysis. RESULTS: All patients were initially clinically without distant metastases (cM0). Seventy-five patients had local recurrence within the prostatic fossa, 32 patients had pelvic nodal plus local recurrence, 117 patients had pelvic nodal recurrence, 51 patients had paraaortic lymph node metastases with/without locoregional recurrence, and 84 patients had bone or visceral metastases with/without locoregional recurrence. Median PSA before MDR was 1.2 ng/mL (range, 0.04-47.5). Additive androgen deprivation therapy (ADT) was given in 35% (125/359) of patients. Median PSA nadir after MDR was 0.23 ng/mL (range, < 0.03-18.30). After a median follow-up of 16 months (1-57), 239/351 (68%) patients had no biochemical recurrence. Patients with distant lymph node and/or distant metastases, the so-called oligo-body cohort, had an overall in-field control of 90/98 (91%) but at the same time, an ex-field progress of 44/96 (46%). In comparison, an ex-field progress was detected in 28/154 (18%) patients with local and/or pelvic nodal recurrence (oligo-pelvis group). Compared with the oligo-pelvis group, there was a significantly lower BRFS in oligo-body patients at the last follow-up. CONCLUSION: Overall, BRFS was dependent on patterns of metastatic disease. Thus, MDR of PSMA PET-positive oligo-metastases can be offered considering that about one-third of the patients progressed within a median follow-up of 16 months.

68Ga-PSMA-PET/CT-directed IGRT/SBRT for oligometastases of recurrent prostate cancer after initial surgery.

Background: We evaluated efficacy and toxicity of 68Ga-PSMA-Positron Emission Tomography/Computed Tomography (PET/CT)-directed stereotactic body radiotherapy and image-guided radiotherapy (SBRT/IGRT) for oligometastases of prostate cancer recurrences after previous surgery.Methods: Nineteen patients were analyzed within a prospective PET-registry study (064/2013BO1) and retrospectively analyzed (807/2017BO2) fulfilling the following inclusion criteria: biochemical recurrence after radical prostatectomy, ≤five 68Ga-PSMA-PET/CT positive lesions. Biochemical control was evaluated with EORTC (European Organization for Research and Treatment of Cancer)- and Phenix-definitions. Toxicity was scored according to CTCAE-criteria v. 4.03.Results: A total of 38 oligometastases (19 patients, 2 with re-treatment) were treated with SBRT/IGRT from October 2014 to July 2017. 68Ga-PSMA-PET/CT-positive lesions were detected on average 39 months (5-139) after prostatectomy (pT2b-3b pN0-1 cM0). Mean PSA (Prostate-specific antigen)-level at time of imaging reached 2.2 ng/mL (range 0.2-10.1). PET/CT-positive lesions were treated with different fractionation schedules reaching biological equivalent doses (BED) of 116.7-230.0 Gy. Concomitant androgen deprivation therapy (ADT) was given in seven patients. After a median follow-up of 17 months (4-42) all patients were alive. Estimated 1-year PSA- control (n = 19) reached 80.8% (Phenix) and 67.5% (EORTC). A PSA-decline (≥50%) was detected in 16/19 patients after radiotherapy. Higher graded G3+-acute toxicity did not occur. Temporary late G3-proctitis was detected in one patient.Conclusions: Reaching of nadir ≤0.1 or 0.2 ng/mL was associated by improved DMFS (distant metastases free survival) and could serve as a surrogate endpoint for RT of oligometastases after initial prostatectomy. Short term effects of 68Ga-PSMA-PET/CT-based ablative radiotherapy for oligometastases demonstrated an acceptable toxicity profile and favorable biochemical response.