Losartan Treatment Attenuates Tumor-induced Myocardial Dysfunction

Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin–angiotensin–aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT) 1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction. Methods and results: Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8 weeks of age. Simultaneously, mice were administered Losartan (10 mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19 days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice. Conclusions: These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation

Power analysis of single-cell RNA-sequencing experiments

Single-cell RNA sequencing (scRNA-seq) has become an established and powerful method to investigate transcriptomic cell-to-cell variation, thereby revealing new cell types and providing insights into developmental processes and transcriptional stochasticity. A key question is how the variety of available protocols compare in terms of their ability to detect and accurately quantify gene expression. Here, we assessed the protocol sensitivity and accuracy of many published data sets, on the basis of spike-in standards and uniform data processing. For our workflow, we developed a flexible tool for counting the number of unique molecular identifiers (https://github.com/vals/umis/). We compared 15 protocols computationally and 4 protocols experimentally for batch-matched cell populations, in addition to investigating the effects of spike-in molecular degradation. Our analysis provides an integrated framework for comparing scRNA-seq protocols.The study was supported by Cancer Research UK grant number C45041/A14953 to A Cvejic and C Labalette, European Research Council project 677501-ZF_Blood to A Cvejic and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute. The ERC grant ThSWITCH to SA Teichmann (grant no. 260507) and a Lister Institute Research Prize to SA Teichmann. KN Natarajan was supported by the Wellcome Trust Strategic Award “Single cell ge nomics of mouse gastrulation”

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Parents\u27 perceptions of medical errors

OBJECTIVES: The purpose of this study was to explore parents\u27 experiences related to events which they believed to be medical errors in their child\u27s care. METHODS: In-depth qualitative interviews were conducted with parents who believed their child had experienced a medical error; responses were analyzed using qualitative methods. RESULTS: In 35 interviews, parents reported a variety of events that they believed to be errors. They described physical harm, emotional distress, life disruptions, changes in behavior, and damage to the relationship with the provider as a result of these events. Most parents felt that they had received no explanation of what had happened, no acknowledgement of the impact of the event, no apology and no acceptance of responsibility by a provider. Parents wanted providers to offer these responses, to express caring for the patient and to feel remorse. They also wanted to know that steps would be taken to prevent recurrences. CONCLUSIONS: Perceived medical errors can impact both the patient and the family in many ways. We recommend that providers acknowledge the full impact of a perceived error and tailor their response to meet the specific needs of the patient and family

Studies to Reduce Unnecessary Medication Use in Frail Older Adults: A Systematic Review

BACKGROUND: Overuse of unnecessary medications in frail older adults with limited life expectancy remains an understudied challenge. OBJECTIVE: To identify intervention studies that reduced use of unnecessary medications in frail older adults. A secondary goal was to identify and review studies focusing on patients approaching end of life. We examined criteria for identifying unnecessary medications, intervention processes for medication reduction, and intervention effectiveness. METHODS: A systematic review of English articles using MEDLINE, EMBASE, and International Pharmaceutical Abstracts from January 1966 to September 2012. Additional studies were identified by searching bibliographies. Search terms included prescription drugs, drug utilization, hospice or palliative care, and appropriate or inappropriate. A manual review of 971 identified abstracts for the inclusion criteria (study included an intervention to reduce chronic medication use; at least 5 participants; population included patients aged at least 65 years, hospice enrollment, or indication of frailty or risk of functional decline-including assisted living or nursing home residence, inpatient hospitalization) yielded 60 articles for full review by 3 investigators. After exclusion of review articles, interventions targeting acute medications, or studies exclusively in the intensive care unit, 36 articles were retained (including 13 identified by bibliography review). Articles were extracted for study design, study setting, intervention description, criteria for identifying unnecessary medication use, and intervention outcomes. RESULTS: The studies included 15 randomized controlled trials, 4 non-randomized trials, 6 pre-post studies, and 11 case series. Control groups were used in over half of the studies (n = 20). Study populations varied and included residents of nursing homes and assisted living facilities (n = 16), hospitalized patients (n = 14), hospice/palliative care patients (n = 3), home care patients (n = 2), and frail or disabled community-dwelling patients (n = 1). The majority of studies (n = 21) used implicit criteria to identify unnecessary medications (including drugs without indication, unnecessary duplication, and lack of effectiveness); only one study incorporated patient preference into prescribing criteria. Most (25) interventions were led by or involved pharmacists, 4 used academic detailing, 2 used audit and feedback reports targeting prescribers, and 5 involved physician-led medication reviews. Overall intervention effect sizes could not be determined due to heterogeneity of study designs, samples, and measures. CONCLUSIONS: Very little rigorous research has been conducted on reducing unnecessary medications in frail older adults or patients approaching end of life

Collaboration or fragmentation? Biodiversity management through the common agricultural policy

We argue that the current system of agri-environment management in the European Common Agricultural Policy is ineffective at conserving biodiversity in part because it promotes fragmentation instead of collaboration of actors, thus hindering coordinated biodiversity management. Actor fragmentation is reinforced by the Common Agricultural Policy (CAP) in three ways: (1) through targeting individual farmers; (2) by creating confusion around coordination roles for increasing numbers of actors; and (3) by failing to engage with barriers to collaboration among farmers. Our findings draw on empirical evidence collected through multi-stakeholder workshops in Germany and Sweden. Our argument adds a different dimension to accepted explanations for the ineffectiveness of CAP for biodiversity management. Traditionally, explanations have focussed on low levels of farmer uptake of relevant measures, or the lack of ecological knowledge informing such measures. The level of actor fragmentation identified here suggests that a fundamental rethink of farmland biodiversity management is needed. We propose a new research agenda to identify more effective governance approaches

Patients and providers view gout differently: a qualitative study

OBJECTIVES: We sought to examine patients\u27 and providers\u27 views on the treatment of gout to better understand why management is suboptimal. METHODS: In-depth telephone interviews were conducted with gout patients (n = 26) who initiated treatment with a urate-lowering drug (ULD) in the previous 6 months and with providers who care for gout patients (n = 15). The interviews were audiotaped and transcribed verbatim. Using qualitative methods, results were analysed and themes were identified. Interviews focused on the acute management, chronic management and prevention and improvement strategies. RESULTS: Providers viewed the majority of patients as having excellent relief with non-steroidal anti-inflammatories, colchicine and glucocorticoids, while some patients felt these medications were ineffective. Providers felt that most patients had a good understanding of the rationale for ULD therapy and that patients responded well. Some patients felt ULDs triggered, worsened or had no impact on their disease. Most providers thought medication adherence was relatively good. Some patients reported discontinuing medications. Discontinuations were largely purposeful and due to clinical or financial concerns. Most providers thought they had adequate skills to teach disease self-management behaviours. Patients requested more information and longer visit times. CONCLUSIONS: Providers view gout as easily managed, while patients report challenges and purposeful non-adherence

Collaboration or fragmentation? Biodiversity management through the common agricultural policy

Drawing on the results of the Transforming Irrigation in Southern Africa project, we assess positive transitions in smallholder irrigation schemes. The project’s theory of change is evaluated. Soil monitoring tools and agricultural innovation platforms were introduced in five irrigation schemes in Mozambique, Tanzania and Zimbabwe. The synergies between these interventions increased both crop yields and profitability. This empowered farmers, improved equity, and accelerated social learning and innovation. The resulting, iterative cycles of change improved governance, sustainability and socio-economic outcomes. The challenges of scaling these interventions up and out are outlined.The authors acknowledge financial support from the ERA NET project MULTAGRI (J.D., J.L., J.F., J.N., T.S., S.V.), Innovation-Incubator at Leuphana University, TM 1.4 Graduate School (S.V.), the VW Stiftung funded project Leverage Points for Sustainability Transformations (D.A.), and the Swedish Research Council FORMAS through the SAPES project (210-2009-1680) (J.D.). We also thank our team of moderators and note-takers at each workshop, led by Ilke Borowski-Maaser, and all participants in the study. Particular thanks go to Christoph Sahrbacher, Amanda Sahrbacher, and Mark Brady for their roles in organising the Saxony and Scania workshops

The hidden Niemann-Pick type C patient : clinical niches for a rare inherited metabolic disease

BACKGROUND : Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups (“clinical niches”) have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. METHODS : Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. FINDINGS : Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. CONCLUSIONS : Several clinical niches have been identified that harbor patients at increased risk of NP-C.Actelion Pharmaceuticals Ltd., Allschwil, Switzerland. From Actelion Pharmaceuticals Ltd.: travel expenses AC, AD, AP, CD-V, CJH, CL, HHK, MT, MW, MP, MS, PB, OB, SD, SL; research funding AP, CL, CD-V, CJH, FT-B, J-CC, MW, OB, PB, RI, SD, TD, TdK; consultancy fees AP, CJH, CL, HHK, MT, MW, OB, PB, SL; speaker honoraria CD-V, MP, MS, PB, SD. MA has received speaker honoraria and travel expenses from Abbvie, TEVA, and UCB. J-CC has received speaker honoraria from Abbvie, travel grants from Abbvie, research funding from, Ipsen, and the Michael J Fox Foundation, and consultancy fees from BMS, Zambon, Pfizer, Amarantus, Clevexel, and Abbvie. CD-V has received research grants, investigator fees, speaker honoraria, and travel expenses from Sanofi Genzyme, Orphan Europe, and Nutricia. SD has received research funding from TEVA. CJH is Director of FYMCA Medical Ltd., has received consultancy fees and travel expenses from Alexion, Amicus, Biomarin, Inventiva, Sanofi Genzyme, and Shire, and has undertaken paid research on behalf of Amicus, Biomarin, Sanofi Genzyme and Shire. SL has received consultancy fees and travel expenses from TEVA, Boehringer, Gruenenthal, and UCB6e. AP has received research funding, consultancy fees and travel expenses from Eli-Lilly, GE Health, and Lundbeck. CT has received speaker honoraria and travel expenses from Abbvie, Zambon, TEVA, and UCB. CV and SK are employees of Actelion Pharmaceuticals Ltd.http://www.tandfonline.com/loi/icmo202018-03-02hj2018Paediatrics and Child Healt

The hidden Niemann-Pick type C patient:Clinical niches for a rare inherited metabolic disease

Background: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups (clinical niches) have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. Methods: Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. Findings: Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. Conclusions: Several clinical niches have been identified that harbor patients at increased risk of NP-C