Federated Learning Survival Model and Potential Radiotherapy Decision Support Impact Assessment for Non-small Cell Lung Cancer Using Real-World Data.

AIMS: The objective of this study was to develop a two-year overall survival model for inoperable stage I-III non-small cell lung cancer (NSCLC) patients using routine radiation oncology data over a federated (distributed) learning network and evaluate the potential of decision support for curative versus palliative radiotherapy. METHODS: A federated infrastructure of data extraction, de-identification, standardisation, image analysis, and modelling was installed for seven clinics to obtain clinical and imaging features and survival information for patients treated in 2011-2019. A logistic regression model was trained for the 2011-2016 curative patient cohort and validated for the 2017-2019 cohort. Features were selected with univariate and model-based analysis and optimised using bootstrapping. System performance was assessed by the receiver operating characteristic (ROC) and corresponding area under curve (AUC), C-index, calibration metrics and Kaplan-Meier survival curves, with risk groups defined by model probability quartiles. Decision support was evaluated using a case-control analysis using propensity matching between treatment groups. RESULTS: 1655 patient datasets were included. The overall model AUC was 0.68. Fifty-eight percent of patients treated with palliative radiotherapy had a low-to-moderate risk prediction according to the model, with survival times not significantly different (p = 0.87 and 0.061) from patients treated with curative radiotherapy classified as high-risk by the model. When survival was simulated by risk group and model-indicated treatment, there was an estimated 11% increase in survival rate at two years (p < 0.01). CONCLUSION: Federated learning over multiple institution data can be used to develop and validate decision support systems for lung cancer while quantifying the potential impact of their use in practice. This paves the way for personalised medicine, where decisions can be based more closely on individual patient details from routine care.

Effectiveness and cost effectiveness of a stress management training for leaders of small and medium sized enterprises - study protocol for a randomized controlled-trial.

BACKGROUND: Leaders in small and medium-sized enterprises (SMEs) are exposed to increased stress as a result of a range of challenges. Moreover, they rarely have the opportunity to participate in stress management trainings. Therefore, KMU-GO (ger: Kleine und mittlere Unternehmen - Gesundheitsoffensive; en: small and medium-sized enterprises - health campaign) aims at conducting and evaluating such a stress management training. The focus of evaluation does not only lie on the effects on leaders participating but also on their employees. METHODS: The study is planned as a 2 × 3 mixed design with two groups (intervention and waiting control group) as a between factor and point in time (at baseline, 6 and 12 months later) as a within factor. We aim at collecting data from N = 200 leaders. Based on the results of a preceding assessment, an already successfully implemented stress management training was adapted to SME needs and now serves as the framework of this intervention. The stress management training comprises one and a half days and is followed by two booster sessions (each 180 min) about 3 and 6 months after the training. The main focus of this intervention lies on specifying leaders stress reactivity while at the same time investigating its effects on employees' mental health. Further dependent variables are leaders´ depression and anxiety scores, effort-reward imbalance, sick days and psychophysiological measures of heart rate variability, hair cortisol, and salivary alpha-amylase. Cost-effectiveness analyses will be conducted from a societal and employers' point of view. DISCUSSION: Stress management is a highly relevant issue for leaders in SMEs. By providing an adequate occupational stress management training, we expect to improve leaders´ and also employees` mental health, thereby preventing economic losses for SMEs and the national economy. However, collecting data from employees about the success of a stress management training of their leader is a highly sensitive topic. It requires a carefully planned proceeding ensuring for example a high degree of transparency, anonymity, and providing team incentives. TRIAL REGISTRATION: The KMU-GO trial is registered at the German Clinical Trial Register (DRKS): DRKS00023457 (05.11.2020).

Review: extended lactation in dairy cattle.

This paper reviews the effects of extended lactation (EXT) as a strategy in dairy cattle on milk production and persistency, reproduction, milk quality, lifetime performance of the cow and finally the economic effects on herd and farm levels as well as the impact on emission of greenhouse gas at product level. Primiparous cows are able to produce equal or more milk per feeding day during EXT compared with a standard 305-d lactation, whereas results for multiparous cows are inconsistent. Cows managed for EXT can achieve a higher lifetime production while delivering milk with unchanged or improved quality properties. Delaying insemination enhances mounting behaviour and allows insemination after the cow's energy balance has become positive. However, in most cases EXT has no effect or a non-significant positive effect on reproduction. The EXT strategy sets off a cascade of effects at herd and farm level. Thus, the EXT strategy leads to fewer calvings and thereby expected fewer diseases, fewer replacement heifers and fewer dry days per cow per year. The optimal lifetime scenario for milk production was modelled to be an EXT of 16 months for first parity cows followed by an EXT of 10 months for later lactations. Modelling studies of herd dynamics indicate a positive effect of EXT on lifetime efficiency (milk per dry matter intake), mainly originating from benefits of EXT on daily milk yield in primiparous cows and the reduced number of replacement heifers. Consequently, EXT also leads to reduced total meat production at herd level. For the farmer, EXT can give the same economic return as a traditional lactation period. At farm level, EXT can contribute to a reduction in the environmental impact of dairy production, mainly as a consequence of the reduced production of beef. A wider dissemination of the EXT concept will be supported by methods to predict which cows may be most suitable for EXT, and clarification of how milking frequency and feeding strategy through the lactation can be organised to support milk yield and an appropriate body condition at the next calving.

Production, partial cash flows and greenhouse gas emissions of simulated dairy herds with extended lactations.

The transition period is the most critical period in the lactation cycle of dairy cows. Extended lactations reduce the frequency of transition periods, the number of calves and the related labour for farmers. This study aimed to assess the impact of 2 and 4 months extended lactations on milk yield and net partial cash flow (NPCF) at herd level, and on greenhouse gas (GHG) emissions per unit of fat- and protein-corrected milk (FPCM), using a stochastic simulation model. The model simulated individual lactations for 100 herds of 100 cows with a baseline lactation length (BL), and for 100 herds with lactations extended by 2 or 4 months for all cows (All+2 and All+4), or for heifers only (H+2 and H+4). Baseline lactation length herds produced 887 t (SD: 13) milk/year. The NPCF, based on revenues for milk, surplus calves and culled cows, and costs for feed, artificial insemination, calving management and rearing of youngstock, was k€174 (SD: 4)/BL herd per year. Extended lactations reduced milk yield of the herd by 4.1% for All+2, 6.9% for All+4, 1.1% for H+2 and 2.2% for H+4, and reduced the NPCF per herd per year by k€7 for All+2, k€12 for All+4, k€2 for H+2 and k€4 for H+4 compared with BL herds. Extended lactations increased GHG emissions in CO2-equivalents per t FPCM by 1.0% for All+2, by 1.7% for All+4, by 0.2% for H+2 and by 0.4% for H+4, but this could be compensated by an increase in lifespan of dairy cows. Subsequently, production level and lactation persistency were increased to assess the importance of these aspects for the impact of extended lactations. The increase in production level and lactation persistency increased milk production of BL herds by 30%. Moreover, reductions in milk yield for All+2 and All+4 compared with BL herds were only 0.7% and 1.1% per year, and milk yield in H+2 and H+4 herds was similar to BL herds. The resulting NPCF was equal to BL for All+2 and All+4 and increased by k€1 for H+2 and H+4 due to lower costs for insemination and calving management. Moreover, GHG emissions per t FPCM were equal to BL herds or reduced (0% to -0.3%) when lactations were extended. We concluded that, depending on lactation persistency, extending lactations of dairy cows can have a positive or negative impact on the NPCF and GHG emissions of milk production.

[Cost effectiveness of GnRH antagonists in patients with prostate cancer and cardiovascular risk : Comparative analysis against Leuprorelin by the Number Needed to Treat]. / Kosteneffektivität von GnRH-Antagonisten bei Patienten mit Prostatakarzinom und kardiovaskulärem Risiko : Vergleichende Analyse gegenüber Leuprorelin anhand der Number Needed to Treat.

BACKGROUND: Recent studies suggest that androgen deprivation therapy (ADT) is associated with increased cardiovascular (CV) risk for patients with hormone-sensitive prostate cancer (PCa) and pre-existing CV disease. This risk seems to be different for the gonadotropin-releasing hormone (GnRH) agonists leuprolide and goserelin and GnRH antagonists, whereas the slightly more expensive GnRH antagonist shows a beneficial risk profile. The present study assesses the cost effectiveness of degarelix compared to leuprolide for PCa patients with increased CV risk. METHODS: This analysis is based on a pooled analysis of six phase III, randomized, controlled trials comparing the GnRH agonists leuprolide and goserelin with the GnRH antagonist degarelix. For the combined endpoint of CV events or death a superiority of degarelix was determined with a Number-Needed-to-Treat of 12. From the perspective of German statutory health insurance, this evaluation estimates and compares the additional drug costs of degarelix treatment to the cost of one (avoided) CV event. The CV event costs were estimated via emergency treatment and transportation, inpatient treatment, and rehabilitation. The difference of these two cost pools divided by 12 yields the average saving per patient and year. RESULTS: For every 12 PCa patients with CV history that are treated with GnRH antagonists to prevent one CV event, there will be additional drug costs in comparison with leuprolide treatment of € 3111 per year. Costs of € 8447 per year are prevented. Therefore, each patient with a history of CV who is treated with degarelix instead of a leuprolide generates savings of € 445 per patient and year. CONCLUSIONS: Compared to leuprolide, degarelix is cost effective for patients with increased CV risk.

Comparison between the TRS-398 code of practice and the TG-51 dosimetry protocol for flattening filter free beams.

Dosimetry protocols for external beam radiotherapy currently in use, such as the IAEA TRS-398 and AAPM TG-51, were written for conventional linear accelerators. In these accelerators, a flattening filter is used to produce a beam which is uniform at water depths where the ionization chamber is used to measure the absorbed dose. Recently, clinical linacs have been implemented without the flattening filter, and published theoretical analysis suggested that with these beams a dosimetric error of order 0.6% could be expected for IAEA TRS-398, because the TPR20,10 beam quality index does not accurately predict the stopping power ratio (water to air) for the softer flattening-filter-free (FFF) beam spectra. We measured doses on eleven FFF linacs at 6 MV and 10 MV using both dosimetry protocols and found average differences of 0.2% or less. The expected shift due to stopping powers was not observed. We present Monte Carlo k Q calculations which show a much smaller difference between FFF and flattened beams than originally predicted. These results are explained by the inclusion of the added backscatter plates and build-up filters used in modern clinical FFF linacs, compared to a Monte Carlo model of an FFF linac in which the flattening filter is removed and no additional build-up or backscatter plate is added.

High spatial resolution dosimetric response maps for radiotherapy ionization chambers measured using kilovoltage synchrotron radiation.

Small circular beams of synchrotron radiation (0.1 mm and 0.4 mm in diameter) were used to irradiate ionization chambers of the types commonly used in radiotherapy. By scanning the chamber through the beam and measuring the ionization current, a spatial map of the dosimetric response of the chamber was recorded. The technique is able to distinguish contributions to the large-field ionization current from the chamber walls, central electrode and chamber stem. Scans were recorded for the NE 2571 Farmer chamber, the PTW 30013, IBA FC65-G Farmer-type chambers, the NE 2611A and IBA CC13 thimble chambers, the PTW 31006 and 31014 pinpoint chambers, the PTW Roos and Advanced Markus plane-parallel chambers, and the PTW 23342 thin-window soft x-ray chamber. In all cases, large contributions to the response arise from areas where the incident beam grazes the cavity surfaces. Quantitative as well as qualitative information about the relative chamber response was extracted from the maps, including the relative contribution of the central electrode. Line scans using monochromatic beams show the effect of the photon energy on the chamber response. For Farmer-type chambers, a simple Monte Carlo model was in good agreement with the measured response.

Diabetes in people with an intellectual disability: a systematic review of prevalence, incidence and impact.

AIMS: To establish the prevalence and incidence of type 1 and type 2 diabetes in people with an intellectual and developmental disability and determine their impact on health and well-being and to appraise the evidence available to inform good practice in diabetes management for people with intellectual and developmental disabilities. METHODS: We conducted separate searches of multiple databases (EMBASE, CINAHL, MEDLINE, PsycINFO, SCOPUS, Web of Science, PUBMED and Cochrane Library) to find relevant articles. RESULTS: A total of 13 studies were identified: 13 addressed the prevalence of diabetes in people with intellectual and developmental disability, three addressed the impact of diabetes on their health and well-being and three addressed the management of diabetes. The prevalence of diabetes in people with intellectual and developmental disability remains uncertain, and the incidence of diabetes in this group of people is unknown. There is some evidence to support the assertion that people with intellectual and developmental disability might be at greater risk of diabetes than the general population. Overall, the quality of the evidence on which to base prevention and management strategies is variable. CONCLUSIONS: There is a paucity of research focusing on the prevalence, incidence and impact of diabetes among people with intellectual and developmental disability. Further research is needed to inform policy and practice in this area and, in particular, work is needed to develop methodologies, evaluation tools, educational resources and diabetes care support services appropriate to the needs of people with intellectual and developmental disability.

Susceptibility of adult and senescent Brown Norway rats to repeated ozone exposure: an assessment of behavior, serum biochemistry and cardiopulmonary function.

Ozone (O3) is a pervasive air pollutant that produces pulmonary and cardiovascular dysfunction and possible neurological dysfunction. Young and old individuals are recognized as being susceptible to O3; however, remarkably little is known about susceptibility with senescence. This study explored the pulmonary, cardiovascular and neurological effects of O3 exposure in adult (4 m) and senescent (20 m) Brown Norway rats exposed to 0 or 0.8 ppm O3 for 6 h, 1 d/week, for 17 weeks. Ventilatory function was assessed 1 and 7 d after each exposure (Buxco). Heart rate, blood pressure (tail cuff) and motor activity were measured biweekly. Blood, aorta and bronchoalveolar lavage fluid (BALF) were analyzed 24 h after the last exposure for pulmonary inflammation, serum biomarkers and aorta mRNA markers of vascular disease. Measures of normal ventilatory function declined following each O3 exposure in both adult and senescent rats, however, senescent rats took weeks to exhibit a decline. Evidence for residual respiratory effects of O3 7 d after exposure in both age groups was observed. O3 had no effect on either heart rate or blood pressure, but decreased motor activity in both age groups. BALF indicated mild neutrophilic inflammation and protein leakage in adults. Age affected 17/58 serum analytes, O3 affected 6/58; 2/58 showed an age-O3 interaction. Leptin, adiponectin, lipocalin and insulin were increased in senescent rats. Overall, adult rats exhibited more immediate effects of episodic O3 than senescent rats. Residual effects were, however, obtained in both ages of rat, especially for ventilatory endpoints.

The effect of very small air gaps on small field dosimetry.

The purpose of this study was to investigate the effect of very small air gaps (less than 1 mm) on the dosimetry of small photon fields used for stereotactic treatments. Measurements were performed with optically stimulated luminescent dosimeters (OSLDs) for 6 MV photons on a Varian 21iX linear accelerator with a Brainlab µMLC attachment for square field sizes down to 6 mm × 6 mm. Monte Carlo simulations were performed using EGSnrc C++ user code cavity. It was found that the Monte Carlo model used in this study accurately simulated the OSLD measurements on the linear accelerator. For the 6 mm field size, the 0.5 mm air gap upstream to the active area of the OSLD caused a 5.3% dose reduction relative to a Monte Carlo simulation with no air gap. A hypothetical 0.2 mm air gap caused a dose reduction >2%, emphasizing the fact that even the tiniest air gaps can cause a large reduction in measured dose. The negligible effect on an 18 mm field size illustrated that the electronic disequilibrium caused by such small air gaps only affects the dosimetry of the very small fields. When performing small field dosimetry, care must be taken to avoid any air gaps, as can be often present when inserting detectors into solid phantoms. It is recommended that very small field dosimetry is performed in liquid water. When using small photon fields, sub-millimetre air gaps can also affect patient dosimetry if they cannot be spatially resolved on a CT scan. However the effect on the patient is debatable as the dose reduction caused by a 1 mm air gap, starting out at 19% in the first 0.1 mm behind the air gap, decreases to <5% after just 2 mm, and electronic equilibrium is fully re-established after just 5 mm.

Improved risk-benefit ratio for topical triamcinolone acetonide in Transfersome in comparison with equipotent cream and ointment: a randomized controlled trial.

BACKGROUND: Transfersome is a drug delivery technology based on highly deformable, ultraflexible lipid vesicles which penetrate the skin when applied non-occlusively. OBJECTIVES: To assess the advantages of this carrier-based formulation in humans, the efficacy and the atrophogenic potential of triamcinolone acetonide (TAC) in Transfersome was compared with commercially available TAC-containing cream and ointment. METHODS: Healthy volunteers were enrolled in double-blind, placebo-controlled clinical trials with random study medication assignment to the test areas. RESULTS: A 10-fold lower dose of TAC in Transfersome(R) (2.5 micro g cm-2) was bioequivalent to 25 micro g cm-2 TAC in conventional formulations as measured by erythema suppression (cream: P = 0.01, ointment: P < 0.001). A skin blanching assay revealed different kinetics of the formulations, with a delayed onset of action of the Transfersome and ointment preparations. Ultrasonic measurements revealed a significantly reduced atrophogenic potential. There was a 12.1% reduction in skin thickness given by TAC in Transfersome compared with a 21.1% reduction given by a bioequivalent dose in TAC cream after a 6-week treatment period (P = 0.007). CONCLUSIONS: Transfersome may significantly improve the risk-benefit ratio of topically applied glucocorticosteroids.

Wire or coated balloon? Searching for an optimal source for intravascular brachytherapy with beta emitters using (32)P as an example.

This study identifies basic dosimetric differences between two designs for intravascular brachytherapy (IVBT) in current clinical practice and ongoing trials and their clinical implications within beta emitting systems using P-32 as an example. The two designs are (i) the wire-type source, where the radioactive source material is confined to a wirelike structure within the vessel lumen, and (ii) the balloon-surface source, where the radioactive source material is distributed over a surface area (balloon-wall) which is brought in close proximity with the vessel wall. Using Monte Carlo simulations with the EGS4 code, the target coverage, the influence of centering errors, and the perturbation of the dose distribution caused by metallic stents have been compared. The radial dose fall-off in the target region was found to be steeper for balloon surface systems compared with wire systems. The inner lumen wall dose for a balloon surface source was 25% higher than that for a wirelike source (2.5 mm vessel diameter). However, the comparably shallower fall-off from wire-type systems is very sensitive to centering uncertainties. A 0.5 mm displacement, for example, will cause the dose to change by a factor of 2 at the inner vessel wall and by a factor of 1.8 at the prescription point. It is shown that the interference from metallic stents is more significant for wire-type systems than it is for balloon-surface-type systems, where double the dose variation beyond the stent at the radial prescription distance may occur. Centering uncertainties dominate the dose perturbation effects for wire-type systems. Balloon-surface-type designs show a more predictable dose distribution that features, however, a higher inner vessel surface dose. Since a direct clinical comparison of systems of both types is not likely, these findings should be considered when interpreting clinical results from treatments with either type of source and, possibly, for future source design.

An automatic system for the assessment of complex medium additives under cultivation conditions.

Complex medium additives such as yeast extract or peptone are often used in industrial cell culture processes to prolong cell growth and/or to improve product formation. The quality of those supplements is dependent on the preparation method and can differ from lot to lot. To guarantee consistent production these different lots have to be tested prior to use in fermentation processes. Because a detailed qualitative and quantitative analysis of all components of such a complex mixture is a very difficult task, another assessment method has to be chosen. The best way to evaluate the effect of such supplements is to monitor cell activity during real cultivation conditions with and without the added supplement lot. A bioreactor-based test system has been developed to determine the oxygen requirement of the cells as a response to the addition of a supplement to be tested under standardized conditions. Investigations were performed with a mouse-mouse hybridoma cell line and yeast extracts as an example for complex medium additives. The results showed differences in the impact between different extract lots and between different concentrations of an extract.

Long-lasting effect of early handling on the peripheral benzodiazepine receptor.

The present study determined the impact of early handling (EH) in rats on behavioral response to environmental stress and on peripheral benzodiazepine receptor (PBR) binding characteristics (Bmax and Kd) in various organs. The behavioral consequences of EH in rats were expressed as increased exploratory activity in an open-field paradigm, when compared with nonhandled control rats. These findings are interpreted in terms of decreased emotionality. The biochemical consequences of EH, in both male and female rats, were expressed as the upregulation of PBR in the adrenal and kidney and the downregulation of gonadal (testis and ovary) PBR. It is possible that the long-lasting adrenal and renal changes in PBR expression in EH rats may enable better regulation of the hypothalamic-pituitary-adrenal axis, renin-angiotensin system, and autonomic nervous system responses to stress in adulthood. The significance of the EH-induced reduction in gonadal PBR for gonadal activity in adulthood is as yet unclear.

Development and health care needs of lesbians.

Lesbians have complained about the lack of awareness and sensitivity of their health care providers, resulting in unnecessary examinations and inappropriate focus on reproductive issues. This study attempted to identify psychosocial and health care needs of lesbians, to assess relationships with primary care providers and disclosure of sexual orientation, and to describe the chronologic features of a sexual identity and lifestyle. An anonymous, self-administered written questionnaire was distributed through a campus lesbian organization. Fifty-three women (median age 23 years) completed the questionnaire. Whereas 60% had disclosed their sexual orientation to their parents, only 31% had "come out" to their health care provider. Of participants who had disclosed their sexual preference to a provider, 27% reported a negative effect on their health care, 57% of participants who never had penile intercourse had annual Papanicolaou smears, and 16% felt pressured in the past to accept birth control from a physician. Lesbian sexuality was associated with several risk factors, such as childhood abuse (20%), alcohol or drug problems (39%), suicide attempts (27%), depression (49%), and physical or verbal abuse at school (34%). Average age of awareness of sexual orientation was 15 years, and average age of first homosexual activity was 17 years. Lesbians are at risk for depression, substance abuse, and suicide attempts. Although most would like to confide in their physician, few do because of fears of negative reactions. Communication must be improved to better address their specific health care needs.

The Super-Spinner: a low cost animal cell culture bioreactor for the CO2 incubator.

The production of small quantities of monoclonal antibodies and recombinant proteins was carried out using a new low cost production system, the Super Spinner. Into a 1 1 standard Duran flask a membrane stirrer equipped with a polypropylene hollow fiber membrane was installed to improve the oxygen supply by bubble-free aeration. The aeration was facilitated by using the CO2 conditioned incubator gas, which was pumped through the membrane stirrer via a small membrane pump. The maximal oxygen transfer rate (OTRmax) of the Super Spinner was detected. For this purpose one spinner flask was equipped with an oxygen electrode. The OTRmax was measured by the dynamic method. The ratio of membrane length to culture volume was adapted corresponding to the oxygen uptake rate of the cells according to the desired cell density. A balanced nutrient supply resulted in an optimal formation and yield of products.