Tolerance and safety of the potentially probiotic strain Lactobacillus rhamnosus PRSF-L477 : a randomised, double-blind placebo-controlled trial in healthy volunteers

In Europe, the species Lactobacillus rhamnosus is currently on the Qualified Presumption of Safety list used by the European Food Safety Authority (EFSA) for internal safety assessment, but according to the EFSA the species should remain a topic of surveillance. In the present study, the safety and tolerance of the potentially probiotic strain L. rhamnosus PRSF-L477 was investigated in a placebo-controlled double-blind volunteer trial following FAO/WHO guidelines. A total of thirty-four subjects received daily doses of 1 x 10(11) colony-forming units (cfu) of L. rhamnosus PRSF-L477 (n 17) or placebo (n 17) for a period of 3 weeks, followed by a wash-out period of another 3 weeks. A questionnaire on gastrointestinal tolerance and a diary was kept daily to record compliance throughout these 6 weeks. Faecal and blood samples were collected for microbiological and haematological analysis. The recorded gastrointestinal symptoms, defecation frequency and stool consistency were not influenced indicating that L. rhamnosus PRSF-L477 was well tolerated. The species L. rhamnosus was detected in the faeces of sixteen out of seventeen subjects of the probiotic group during the intervention period. Using pulsed-field gel electrophoresis, re-isolates of L. rhamnosus PRSF-L477 were confirmed in nine of these subjects. Antibiotic susceptibility profiles of these re-isolates were unchanged compared with PRSF-L477. No clinically relevant changes in blood parameters such as liver and kidney function and no serious adverse events appeared during and after administration. Therefore, we conclude that L. rhamnosus PRSF-L477 can safely be administrated to healthy subjects at a daily dose of 1 x 10(11) cfu

Оправдание науки

textabstractBackground With an ageing society and increasing retirement ages, it is important to understand how employability can be promoted in older workers with health problems. The current study aimed to determine whether (1) different chronic health problems predict transitions from paid employment to disability benefits, unemployment and early retirement, and (2) how workrelated factors modify these associations. Methods Self-report questionnaire data was used from the Dutch longitudinal Study on Transitions in Employment, Ability and Motivation with 3 years of follow-up (2010-2013), among employees aged 45-64 years (N=8149). The influence of baseline chronic health problems and work-related factors on transitions from paid employment to disability benefits, unemployment and early retirement during follow-up was estimated in a competing risks proportional hazards model. Relative excess risk of transitions due to the interaction between chronic health problems and workrelated factors was assessed. Results Severe headache, diabetes mellitus and musculoskeletal, respiratory, digestive and psychological health problems predicted an increased risk of disability benefits (HR range 1.78-2.79). Circulatory (HR=1.35) and psychological health problems (HR=2.58) predicted unemployment, and musculoskeletal (HR=1.23) and psychological health problems (HR=1.57) predicted early retirement. Work-related factors did not modify the influence of health problems on unemployment or early retirement. Psychosocial work-related factors, especially autonomy, modified the influence of health problems on disability benefits. Specifically, among workers with health problems, higher autonomy, higher support and lower psychological job demands reduced the risk of disability benefits by 82%, 49%, and 11%, respectively. Conclusions All health problems affected disability benefits to a similar extent, but psychological health problems especially predicted unemployment and early retirement. For older workers with health problems, promoting an optimal work environment has the potential to contribute to sustainable employment

A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation

We assessed the effectiveness and safety of 3 yr combined GH and GnRH agonist (GnRHa) treatment in a randomized controlled study in children with idiopathic short stature (ISS) or intrauterine growth retardation (IUGR). Gonadal suppression, GH reserve, and adrenal development were assessed by hormone measurements in both treated children and controls during the study period. Thirty-six short children, 24 girls (16 ISS/8 IUGR) and 12 boys (8 ISS/4 IUGR), with a height SD score of -2 SD or less in early puberty (girls, B2-3; boys, G2-3), were randomly assigned to treatment (n = 18) with GH (genotropin 4 IU/m(2). day) and GnRHa (triptorelin, 3.75 mg/28 days) or no treatment (n = 18). At the start of the study mean (SD) age was 11.4 (0.56) or 12.2 (1.12) yr whereas bone age was 10.7 (0.87) or 10.9 (0.63) yrs in girls and boys, respectively. During 3 yr of study height SD score for chronological age did not change in both treated children and controls, whereas a decreased rate of bone maturation after treatment was observed [mean (SD) 0.55 (0.21) 'yr'/yr vs. 1.15 (0.37) 'yr'/yr in controls, P < 0.001, girls and boys together]. Height SD score for bone age and predicted adult height increased significantly after 3 yr of treatment; compared with controls the predicted adult height gain was 8.0 cm in girls and 10.4 cm in boys. Furthermore, the ratio between sitting height/height SD score decreased significantly in treated children, whereas body mass index was not influenced by treatment. Puberty was effectively arrested in the treated children, as was confirmed by physical examination and prepubertal testosterone and estradiol levels. GH-dependent hormones including serum insulin-like growth factor I and II, carboxy terminal propeptide of type I collagen, amino terminal propeptide of type III collagen, alkaline phosphatase, and osteocalcin were not different between treated children and controls during the study period. Thus, a GH dose of 4 IU/m(2) seems adequate for stabilization of the GH reserve and growth in these GnRHa-treated children. We conclude that 3 yr treatment with GnRHa was effective in suppressing pubertal development and skeletal maturation, whereas the addition of GH preserved growth velocity during treatment. This resulted in a considerable gain in predicted adult height, without demonstrable side effects. Final height results will provide the definite answer on the effectiveness of this combined treatment

Міські проекції в ранній ліриці Лесі Українки

У статті вивчаються особливості художнього осмислення міського простору в ранній ліриці Лесі Українки. Звертається увага на те, що в процесі свого літературного становлення поетеса використала досвід різних традицій. Сентиментально налаштована героїня її творів оцінює місто як меркантильне, нелюдяне, байдуже до природної краси. В окремих поезіях переважає романтичний погляд: міський простір розглядається як тісний і задушливий, такий, що нівелює неповторність окремої особистості. Низка творів авторки репрезентує погодження неокласичних і романтичних тенденцій. Ключові слова: сентименталізм, романтизм, неокласицизм, лірика.В предлагаемой статье исследуются особенности художественного осмысления городского пространства в ранней лирике Леси Украинки. Учитывается тот факт, что в процессе своего литературного становления поэтесса использовала опыт различных традиций. Сентиментально настроенная героиня ее произведений оценивает город как меркантильный, исполненный безразличия к естественной красоте. В отдельных поэзиях преобладает романтический взгляд: городское пространство рассматривается как тесное, нивелирующее неповторимость отдельной личности. Ряд произведений Леси Украинки представляет взаимодействие романтических и неоклассических тенденций. Ключевые слова: сентиментализм, романтизм, неоклассицизм, лирика.In the article the features of early lyric poetry of Lesya Ukrainka are explored. That is taken into account, that in the process of the literary becoming a poetess used experience of different traditions. The sentimentally adjusted heroine gives preference to natural beauty. A romantic look prevails in separate poetries: urbanism space appears as incompatible with the uniqueness of individual. Romantic and neoclassical tendencies co-operate in a number of works of Lesya Ukrainka. Keywords: sentimentalizm, romanticism, neoclassicism, lyric poetry

Cellpy – an open-source library for processing and analysis of battery testing data

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Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors

Introduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs. Areas covered: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal\u2013epithelial transition factor (MET) amplification, epithelial\u2013mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 orpoly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation. Conclusion: Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC

Mapping and Handling Conflicts of Interest in Deceased Organ Donation: How to Handle Ethical Issues and Build Trust in the Healthcare Team

It has been suggested that there is a significant conflict of interest between providing best care for the dying patient and a subsidiary role in facilitating the donation process. Should healthcare professionals who are involved in a patient’s care and determination of death also be involved in discussing donation with families? If they are involved, should they disclose this potential conflict of interest? In this paper we address the issue of conflicts of interest in organ donation by examining current best practice in four European countries (Sweden, Netherlands, the United Kingdom and Spain) and discuss whether having clear separation of roles in order to avoid conflicts is preferable to having the same physician (or team) handle both the dying process and donation. We also analyse the benefits and burdens of disclosing such potential conflicts

Value of screening and follow-up brain MRI scans in patients with metastatic melanoma

BACKGROUND: Novel treatments make long‐term survival possible for subsets of patients with melanoma brain metastases. Brain magnetic resonance imaging (MRI) may aid in early detection of brain metastases and inform treatment decisions. This study aimed to determine the impact of screening MRI scans in patients with metastatic melanoma and follow‐up MRI scans in patients with melanoma brain metastases. METHODS: This retrospective cohort study included patients diagnosed with metastatic melanoma or melanoma brain metastases between June 2015 and January 2018. The impact of screening MRI scans was evaluated in the first 2 years after metastatic melanoma diagnosis. The impact of follow‐up MRI scans was examined in the first year after brain metastases diagnosis. The number of MRI scans, scan indications, scan outcomes, and changes in treatment strategy were analyzed. RESULTS: In total, 116 patients had no brain metastases at the time of the metastatic melanoma diagnosis. Twenty‐eight of these patients (24%) were subsequently diagnosed with brain metastases. Screening MRI scans detected the brain metastases in 11/28 patients (39%), of which 8 were asymptomatic at diagnosis. In the 96 patients with melanoma brain metastases, treatment strategy changed after 75/168 follow‐up MRI scans (45%). In patients treated with immune checkpoint inhibitors, the number of treatment changes after follow‐up MRI scans was lower when patients had been treated longer. CONCLUSION(S): Screening MRI scans aid in early detection of melanoma brain metastases, and follow‐up MRI scans inform treatment strategy. In patients with brain metastases responding to immune checkpoint inhibitors, treatment changes were less frequently observed after follow‐up MRI scans. These results can inform the development of brain imaging protocols for patients with immune checkpoint inhibitor sensitive tumors

Clinical utility of circulating tumor DNA as a response and follow-up marker in cancer therapy

Response evaluation for cancer treatment consists primarily of clinical and radiological assessments. In addition, a limited number of serum biomarkers that assess treatment response are available for a small subset of malignancies. Through recent technological innovations, new methods for measuring tumor burden and treatment response are becoming available. By utilization of highly sensitive techniques, tumor-specific mutations in circulating DNA can be detected and circulating tumor DNA (ctDNA) can be quantified. These so-called liquid biopsies provide both molecular information about the genomic composition of the tumor and opportunities to evaluate tumor response during therapy. Quantification of tumor-specific mutations in plasma correlates well with tumor burden. Moreover, with liquid biopsies, it is also possible to detect mutations causing secondary resistance during treatment. This review focuses on the clinical utility of ctDNA as a response and follow-up marker in patients with non-small cell lung cancer, melanoma, colorectal cancer, and breast cancer. Relevant studies were retrieved from a literature search using PubMed database. An overview of the available literature is provided and the relevance of ctDNA as a response marker in anti-cancer therapy for clinical practice is discussed. We conclude that the use of plasma-derived ctDNA is a promising tool for treatment decision-making based on predictive testing, detection of resistance mechanisms, and monitoring tumor response. Necessary steps for translation to daily practice and future perspectives are discussed