Pessary treatment for pelvic organ prolapse and health-related quality of life: a review

Pessaries have been used to treat women with pelvic organ prolapse (POP) since the beginning of recorded history. This review aims to assess the effect of pessary treatment on the disease-specific, health-related quality of life in women with pelvic organ prolapse. After a Medline search using the Mesh term ‘pessary’ and critical appraisal, 41 articles were selected and used in this review. Pessaries are widely used to treat pelvic organ prolapse. It is minimally invasive and appears to be safe. Although there is evidence that the use of pessaries in the treatment of pelvic organ prolapse is effective in alleviating symptoms and that patient satisfaction is high, the follow-up in many published papers is short, and the use of validated urogynaecological questionnaires is limited. Comparison with surgical treatment of pelvic organ prolapse is rare and not assessed in a randomised controlled trial

Glioblastoma Multiforme in the Posterior Cranial Fossa in a Patient with Neurofibromatosis Type I

Patients with Neurofibromatosis type 1 (NF1) have an increased risk of developing neoplasms. The most common brain tumors, found in 15%–20% of NF1 patients, are hypothalamic-optic gliomas, followed by brainstem and cerebellar pilocytic astrocytomas. These tumors generally have a benign nature. NF1 patients are predisposed to a 5-fold increased incidence of high-grade astrocytomas, which are usually located in supratentorial regions of the brain. We present an NF1 patient who developed a high-grade astrocytoma in the posterior fossa and discuss possible pathophysiological mechanisms

Clinical benefit of systemic therapies for recurrent ovarian cancer-ESMO-MCBS scores

BACKGROUND: Licensed systemic treatment options for platinum-sensitive recurrent ovarian cancer are platinum-based chemotherapy and maintenance treatment with bevacizumab and poly (ADP-ribose) polymerase inhibitors. For platinum-resistant disease, several non-platinum options are available. We aimed to assess the clinical benefit of these treatments according to the European Society of Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS). MATERIALS AND METHODS: A PubMed search was carried out including all studies evaluating systemic treatment of recurrent epithelial ovarian cancer, from 1990 onwards. Randomised trials with an adequate comparator and design showing a statistically significant benefit of the study arm were independently scored by two blinded observers using the ESMO-MCBS. RESULTS: A total of 1127 papers were identified, out of which 61 reported results of randomised trials of sufficient quality. Nineteen trials showed statistically significant results and the studied treatments were graded according to ESMO-MCBS. Only three treatments showed substantial benefit (score of 4 on a scale of 1-5) according to the ESMO-MCBS: platinum-based chemotherapy with paclitaxel in the platinum-sensitive setting and the addition of bevacizumab to chemotherapy in the platinum-resistant setting. The WEE1 inhibitor adavosertib (not licensed) also scores a 4, based on a recent small phase II study. Assessment of quality-of-life data and toxicity using the ESMO-MCBS showed to be complex, which should be taken into account in using this score for clinical decision making. CONCLUSION: Only a few licensed systemic therapies for recurrent ovarian cancer show substantial clinical benefit based on ESMO-MCBS scores. Trials demonstrating overall survival benefit are sparse

Representation of older patients in the safety analysis of protein kinase inhibitor registration studies

INTRODUCTION: Older patients (≥65 years old) make up the majority of the cancer population. Older patients seem to experience more adverse events (AEs) from protein kinase inhibitors (PKIs) in clinical practice. Yet they are underrepresented in clinical trials. We aimed to evaluate whether age-related safety differences were described at authorization of PKIs. Representation of older patients in registration studies was also evaluated.MATERIALS AND METHODS: European Public Assessment Reports (EPARs) of PKIs authorized between 2010 and 2015 were evaluated for the description of age-related safety- and pharmacokinetic differences. The International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use (ICH) E7 guideline was applied to EPARs to assess the representation of older patients. Study results were presented descriptively.RESULTS: Eighteen PKIs with 19 EPARs were analyzed. Age-related safety differences were described in 14 out of 19 EPARs, and age-related pharmacokinetic differences in 1 out of 19 EPARs. More than 100 older patients were included in half of the studies. Older patients were not excluded solely by age, although other inclusion and exclusion criteria negatively influenced enrollment of older patients. None of the PKIs met all criteria from the ICH E7 guideline.DISCUSSION: Age-related safety differences are described for most PKIs. Older patients were underrepresented in PKI registration studies. Adequate representation of older patients in clinical trials for PKIs is vital, since they make up most of the cancer population.</p

Generating a checking sequence with a minimum number of reset transitions

Given a finite state machine M, a checking sequence is an input sequence that is guaranteed to lead to a failure if the implementation under test is faulty and has no more states than M. There has been much interest in the automated generation of a short checking sequence from a finite state machine. However, such sequences can contain reset transitions whose use can adversely affect both the cost of applying the checking sequence and the effectiveness of the checking sequence. Thus, we sometimes want a checking sequence with a minimum number of reset transitions rather than a shortest checking sequence. This paper describes a new algorithm for generating a checking sequence, based on a distinguishing sequence, that minimises the number of reset transitions used.This work was supported in part by Leverhulme Trust grant number F/00275/D, Testing State Based Systems, Natural Sciences and Engineering Research Council (NSERC) of Canada grant number RGPIN 976, and Engineering and Physical Sciences Research Council grant number GR/R43150, Formal Methods and Testing (FORTEST)

Guiding cities under increased droughts: The limits to sustainable urban futures

Climate change is likely to increase droughts. The vulnerability of cities to droughts is increasing worldwide. Policy responses from cities to droughts lack consideration of long-term climatic and socio-economic scenarios, and focus on short-term emergency actions that disregard sustainability in the connected regional and river basin systems. We aim to explore the dynamics of the water-energy-land nexus in urban systems suffering increased climate change-related droughts, and their implications for sustainability. We complement a case study with a literature review providing cross-regional insights, and detail pervasive knowledge, policy and ambition gaps in the interaction between cities and droughts. We show that water availability with low emissions, without compromising ecosystems and with low costs to society, poses a local-scale limit to sustainable urban growth, a new concept delineating the limits to growth in cities. We conclude that urban and river basin planners need to institutionalize transparency and cross-sectoral integration in multi-sector partnerships, to consider long-term land use planning together with water and energy, and to apply integrated climate services to cities. Our study reveals the importance of including land, water and energy in long-term urban planning, and to connect them with the county, region, river basin and global scales. © 2021 The Author(s)The authors would like to express their gratitude for limited contributions, comments and discussions that helped to improve the manuscript to Muhamad Bahri, Jörg Cortekar, Mirabela Marin, Serban Octavian Davidescu, Iñaki Torres Cobián, and to two anonymous reviewers that helped to substantially improve the manuscript. Valuable feedback obtained in two conference sessions co‑lead by some of the authors (at Adaptation Futures 2018 in Cape Town, and at the 4th European Climate Change Adaptation conference, in Lisbon in 2019) is acknowledged. The authors acknowledge financial support from the project CLISWELN funded by ERA4CS. ERA4CS is an ERA-NET initiated by JPI Climate, and CLISWELN is funded by BMBF (DE), UEFISCDI (RO), BMBWF and FFG (AT), and MINECO (ES), with co-funding from the European Union (Grant 690462 ). This paper and the content included in it do not represent the opinion of the European Union, and the European Union is not responsible for any use that might be made of its content. Marta OlazabalThe authors would like to express their gratitude for limited contributions, comments and discussions that helped to improve the manuscript to Muhamad Bahri, Jörg Cortekar, Mirabela Marin, Serban Octavian Davidescu, Iñaki Torres Cobián, and to two anonymous reviewers that helped to substantially improve the manuscript. Valuable feedback obtained in two conference sessions co‑lead by some of the authors (at Adaptation Futures 2018 in Cape Town, and at the 4th European Climate Change Adaptation conference, in Lisbon in 2019) is acknowledged. The authors acknowledge financial support from the project CLISWELN funded by ERA4CS. ERA4CS is an ERA-NET initiated by JPI Climate, and CLISWELN is funded by BMBF (DE), UEFISCDI (RO), BMBWF and FFG (AT), and MINECO (ES), with co-funding from the European Union (Grant 690462 ). This paper and the content included in it do not represent the opinion of the European Union, and the European Union is not responsible for any use that might be made of its content. Marta Olazaba

Uniform and Complementary Social Interaction:Distinct Pathways to Solidarity

We examine how different forms of co-action give rise to feelings of solidarity. We propose that (a) coordinated action elicits a sense of solidarity, and (b) the process through which such solidarity emerges differs for different forms of co-action. We suggest that whether solidarity within groups emerges from uniform action (e.g. synchronizing, as when people speak in unison) or from more complementary forms of action (e.g. alternating, when speaking in turns) has important consequences for the emergent position of individuals within the group. Uniform action relies on commonality, leaving little scope for individuality. In complementary action each individual makes a distinctive contribution to the group, thereby increasing a sense of personal value to the group, which should contribute to the emergence of solidarity. The predictions receive support from five studies, in which we study groups in laboratory and field settings. Results show that both complementary and uniform co-action increase a sense of solidarity compared to control conditions. However, in the complementary action condition, but not in the uniform action (or synchrony) condition, the effect on feelings of solidarity is mediated by a sense of personal value to the group

Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease?

Pathogenesis and treatment of chronic pulmonary disease

Functional characterisation of bone marrow-derived mesenchymal stromal cells from COPD patients

ABSTRACT Autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs) are evaluated forclinical use in chronic obstructive pulmonary disease (COPD) patients, but it is unclear whether COPDaffects BM-MSCs.To investigate this, BM-MSCs from nine COPD patients and nine non-COPD age-matched controls werecompared with regard to immunophenotype, growth and differentiation potential, and migration capacity.Other functional assays included the response to pro-inflammatory stimuli and inducers of the nuclearfactor (erythroid derived 2)-like 2 antioxidant response element (Nrf2-ARE) pathway, and effects on NCIH292airway epithelial cells.No significant differences were observed in terms of morphology, proliferation and migration, except forincreased adipocyte differentiation potential in the COPD group. Both groups were comparable regardingmRNA expression of growth factors and inflammatory mediators, and in their potential to induce mRNAexpression of epidermal growth factor receptor ligands in NCI-H292 airway epithelial cells. MSCs fromCOPD patients secreted more interleukin-6 in response to pro-inflammatory stimuli. Activation of the Nrf2-ARE pathway resulted in a comparable induction of mRNA expression of four target genes, but theexpression of the NAD(P)H:quinone oxidoreductase 1 gene NQO1 was lower in MSCs from COPD patients.The observation that MSCs from COPD patients are phenotypically and functionally comparable tothose from non-COPD controls implies that autologous MSCs can be considered for use in the setting ofclinical trials as a treatment for COPD.Pathogenesis and treatment of chronic pulmonary disease

Effectiveness and toxicity of lenvatinib in refractory thyroid cancer:Dutch real-life data

Objective: The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial. Methods: From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies. Results: A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade >= 3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0-15.5) and 18.3 (95% CI: 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04). Conclusions: PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life population and the SELECT study population regarding patient characteristics should be taken into account