At identical isowork rates, ageing influences cardiorespiratory adaptations in COPD out-patients

SummaryPurposeTo determine the extent to which younger COPD patients improve their cardiorespiratory function during exercise in comparison with older COPD patients, as a result of exercise training.MethodsThirty-nine COPD patients underwent an exercise program. They were divided into two groups: a younger group (57.2±1.0 years, n=18 patients) and an older group (68.8±0.6 years, n=21 patients). Forced expiratory volume in 1s was lower than 55% of the predicted value for all patients.ResultsAfter training, V˙O2 symptom-limited significantly improved by 10.3% and 8.4% for the younger and older COPD patients, respectively (P<0.05). Peak power significantly improved by 25.2% and 17.8% in the younger and older groups, respectively (P<0.05) with a greater improvement for the younger group (P<0.05). At submaximal exercise, ventilation and heart rate significantly decreased after training in the younger COPD patients (P<0.05) with no significant modification in the older COPD patients.ConclusionsThe results suggest that all patients with COPD benefit from exercise rehabilitation at maximal exercise workload, however, according to their age, submaximal cardiorespiratory adaptations were greater in younger patients

STOPP/START interventions to improve medicines management for people aged 65 years and over: a realist synthesis

Background Drug-related problems and potentially inappropriate prescribing impose a huge burden on patients and the health-care system. The most widely used tools for appropriate prescription in older adults in England and in other European countries are the Screening Tool of Older People’s Prescriptions (STOPP)/Screening Tool to Alert to the Right Treatment (START) tools. STOPP/START tools support medicines optimisation for older adults. Objectives To identify, test and refine the programme theories underlying how interventions based on the STOPP/START tools are intended to work, for whom, in what circumstances and why, as well as the resource use and cost requirements or impacts. Design A realist synthesis. Setting Primary care, hospital care and nursing homes. Patients Patients aged ≥ 65 years. Interventions Any intervention based on the use of the STOPP/START tools. Review methods Database and web-searching was carried out to retrieve relevant evidence to identify and test programme theories about how interventions based on the use of the STOPP/START tools work. A project reference group made up of health-care professionals, NHS decision-makers, older people, carers and members of the public was set up. In phase 1 we identified programme theories about STOPP/START interventions on how, for whom, in what contexts and why they are intended to work. We searched the peer-reviewed and grey literature to identify documents relevant to the research questions. We interviewed experts in the field in our reference group to gain input on our list of candidate context–mechanism–outcome configurations, to identify additional context–mechanism–outcome configurations and to identify additional literature and/or relevant concepts. In phase 2 we reviewed and synthesised relevant published and unpublished empirical evidence and tested the programme theories using evidence from a larger set of empirical studies. Results We developed a single logic model structured around three key mechanisms: (1) personalisation, (2) systematisation and (3) evidence implementation. Personalisation: STOPP/START-based interventions are based on shared decision-making, taking into account patient preferences, experiences and expectations (mechanisms), leading to increased patient awareness, adherence, satisfaction, empowerment and quality of life (outcomes). Systematisation: STOPP/START tools provide a standardised/systematic approach for medication reviews (mechanisms), leading to changes in professional and organisational culture and burden/costs (outcomes). Evidence implementation: delivery of STOPP/START-based interventions is based on the implementation of best evidence (mechanisms), reducing adverse outcomes through appropriate prescribing/deprescribing (outcomes). For theory testing, we identified 40 studies of the impact of STOPP/START-based interventions in hospital settings, nursing homes, primary care and community pharmacies. Most of the interventions used multiple mechanisms. We found support for the impact of the personalisation and evidence implementation mechanisms on selected outcome variables, but similar impact was achieved by interventions not relying on these mechanisms. We also observed that the impact of interventions was linked to the proximity of the selected outcomes to the intervention in the logic model, resulting in a clearer benefit for appropriateness of prescribing, adverse drug events and prescription costs. Limitations None of the available studies had been explicitly designed for evaluating underlying causal mechanisms, and qualitative information was sparse. Conclusions No particular configuration of the interventions is associated with a greater likelihood of improved outcomes in given settings. Study registration This study is registered as PROSPERO CRD42018110795. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 23. See the NIHR Journals Library website for further project information

Semi-Synthetic Analogues of Cryptolepine as a Potential Source of Sustainable Drugs for the Treatment of Malaria, Human African Trypanosomiasis and Cancer

YesThe prospect of eradicating malaria continues to be challenging in the face of increasing parasite resistance to antimalarial drugs so that novel antimalarials active against asexual, sexual, and liver-stage malaria parasites are urgently needed. In addition, new antimalarials need to be affordable and available to those most in need and, bearing in mind climate change, should ideally be sustainable. The West African climbing shrub Cryptolepis sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid, cryptolepine (1), has been shown to have antimalarial properties, and the synthetic analogue 2,7-dibromocryptolepine (2) is of interest as a lead toward new antimalarial agents. Cryptolepine (1) was isolated using a two-step Soxhlet extraction of C. sanguinolenta roots, followed by crystallization (yield 0.8% calculated as a base with respect to the dried roots). Semi-synthetic 7-bromo- (3), 7, 9-dibromo- (4), 7-iodo- (5), and 7, 9-dibromocryptolepine (6) were obtained in excellent yields by reaction of 1 with N-bromo- or N-iodosuccinimide in trifluoroacetic acid as a solvent. All compounds were active against Plasmodia in vitro, but 6 showed the most selective profile with respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC50 = 0.25 µM, SI = 113; late stage, gametocytes, IC50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites IC50 = 6.13 µM, SI = 4.6. Compounds 3–6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC50 = 0.11 µM). In addition, 3–6 potently inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the most selective (IC50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type ovarian cancer cells as well as adriamycin-resistant and, except for 5, cisplatin-resistant ovarian cancer cells. In an acute oral toxicity test in mice, 3–6 did not exhibit toxic effects at doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C. sanguinolenta may be utilized as a sustainable source of novel compounds that may lead to the development of novel agents for the treatment of malaria, African trypanosomiasis, and cancer

Global Retinoblastoma Presentation and Analysis by National Income Level

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4) were female. Most patients (n = 3685 84.7%) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 62.8%), followed by strabismus (n = 429 10.2%) and proptosis (n = 309 7.4%). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 95% CI, 12.94-24.80, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 95% CI, 4.30-7.68). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs. © 2020 American Medical Association. All rights reserved