Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab

Background: Pertuzumab, a human epidermal growth factor receptor (HER) 2 dimerization inhibitor, has demonstrated promising efficacy in combination with trastuzumab in patients with metastatic breast cancer. As HER signaling pathways are not only involved in oncogenesis, but also in myocardial homeostasis, an analysis of cardiac safety data was undertaken in a large group of patients treated with pertuzumab. Patients and methods: A complete database of patients treated with full-dose pertuzumab was used to describe the incidence of asymptomatic left ventricular systolic dysfunction (LVSD) and symptomatic heart failure (HF). Results: Information for 598 unique patients was available for the current analysis. Of the patients treated with pertuzumab alone (n = 331) or pertuzumab in combination with a non-anthracycline-containing cytotoxic (n = 175) or trastuzumab (n = 93), 23 (6.9%), 6 (3.4%), and 6 (6.5%), respectively, developed asymptomatic LVSD and 1 (0.3%), 2 (1.1%), and 1 (1.1%), respectively, displayed symptomatic HF. None of the 15 patients receiving both pertuzumab and erlotinib demonstrated LVSD. Conclusions: Patients treated with pertuzumab experienced relatively low levels of asymptomatic LVSD or symptomatic HF. There was no notable increase in cardiac side-effects when pertuzumab was given in combination with other anticancer agent

Open-label comparative clinical study of chlorproguanil-dapsone fixed dose combination (Lapdap) alone or with three different doses of artesunate for uncomplicated Plasmodium falciparum malaria.

UNLABELLED: The objective of this study was to determine the appropriate dose of artesunate for use in a fixed dose combination therapy with chlorproguanil-dapsone (CPG-DDS) for the treatment of uncomplicated falciparum malaria. METHODS: Open-label clinical trial comparing CPG-DDS alone or with artesunate 4, 2, or 1 mg/kg at medical centers in Blantyre, Malawi and Farafenni, The Gambia. The trial was conducted between June 2002 and February 2005, including 116 adults (median age 27 years) and 107 children (median age 38 months) with acute uncomplicated Plasmodium falciparum malaria. Subjects were randomized into 4 groups to receive CPG-DDS alone or plus 4, 2 or 1 mg/kg of artesunate once daily for 3 days. Assessments took place on Days 0-3 in hospital and follow-up on Days 7 and 14 as out-patients. Efficacy was evaluated in the Day 3 per-protocol (PP) population using mean time to reduce baseline parasitemia by 90% (PC90). A number of secondary outcomes were also included. Appropriate artesunate dose was determined using a pre-defined decision matrix based on primary and secondary outcomes. Treatment emergent adverse events were recorded from clinical assessments and blood parameters. Safety was evaluated in the intent to treat (ITT) population. RESULTS: In the Day 3 PP population for the adult group (N = 85), mean time to PC90 was 19.1 h in the CPG-DDS group, significantly longer than for the +artesunate 1 mg/kg (12.5 h; treatment difference -6.6 h [95%CI -11.8, -1.5]), 2 mg/kg (10.7 h; -8.4 h [95%CI -13.6, -3.2]) and 4 mg/kg (10.3 h; -8.7 h [95%CI -14.1, -3.2]) groups. For children in the Day 3 PP population (N = 92), mean time to PC90 was 21.1 h in the CPG-DDS group, similar to the +artesunate 1 mg/kg group (17.7 h; -3.3 h [95%CI -8.6, 2.0]), though the +artesunate 2 mg/kg and 4 mg/kg groups had significantly shorter mean times to PC90 versus CPG-DDS; 14.4 h (treatment difference -6.4 h [95%CI -11.7, -1.0]) and 12.8 h (-7.4 h [95%CI -12.9, -1.8]), respectively. An analysis of mean time to PC90 for the Day 14 PP and ITT populations was consistent with the primary analysis. Treatment emergent, drug-related adverse events were experienced in 35.3% (41/116) of adults and 70.1% (75/107) of children; mostly hematological and gastroenterological. The nature and incidence of adverse events was similar between the groups. No dose-related changes in laboratory parameters were observed. Nine serious adverse events due to any cause occurred in five subjects including two cases of hemolysis believed to be associated with drug treatment (one adult, one child). One adult died of anaphylactic shock, not associated with investigational therapy. CONCLUSIONS: CPG-DDS plus artesunate demonstrated advantages over CPG-DDS alone for the primary efficacy endpoint (mean time to PC90) except in children for the 1 mg/kg artesunate dose. Based on a pre-defined decision matrix, the primary endpoint in the child group supported an artesunate dose of 4 mg/kg. Secondary endpoints also supported a 4 mg/kg artesunate dose to take forward into the remainder of the development program. TRIAL REGISTRATION: ClinicalTrials.gov NCT00519467

‘Triple wins’ or ‘triple faults’? Analysing the equity implications of policy discourses on climate-smart agriculture (CSA)

This paper analyses contrasting discourses of ‘climate-smart agriculture’ (CSA) for their implications on control over and access to changing resources in agriculture. One of the principal areas of contestation around CSA relates to equity, including who wins and who loses, who is able to participate, and whose knowledge and perspectives count in the process. Yet to date, the equity implications of CSA remain an under-researched area. We apply an equity framework centred on procedure, distribution and recognition, to four different discourses. Depending on which discourses are mobilised, the analysis helps to illuminate: (1) how CSA may transfer the burden of responsibility for climate change mitigation to marginalised producers and resource managers (distributive equity); (2) how CSA discourses generally fail to confront entrenched power relations that may constrain or block the emergence of more ‘pro-poor’ forms of agricultural development, adaptation to climate change, or carbon sequestration and storage (procedural equity); (3) how CSA discourses can have tangible implications for the bargaining power of the poorest and most vulnerable groups (recognition). The paper contributes to work showing the need for deeper acknowledgement of the political nature of the transformations necessary to address the challenges caused by a changing climate for the agricultural sector

TMEDA in Iron‐Catalyzed Hydromagnesiation: Formation of Iron(II)‐Alkyl Species for Controlled Reduction to Alkene‐Stabilized Iron(0)

N,N,N’,N’‐Tetramethylethylenediamine (TMEDA) has been one of the most prevalent and successful additives used in iron‐catalysis, finding application in reactions as diverse as cross‐coupling, C‐H activation and borylation. However, the role that TMEDA plays in these reactions remains largely undefined. Herein, studying the iron‐catalyzed hydromagnesiation of styrene derivatives using TMEDA has provided molecular‐level insight into the role of TMEDA in achieving effective catalysis. Key is the initial formation of TMEDA‐iron(II) alkyl species which undergo a controlled reduction to selectively form catalytically active styrene‐stabilized iron(0)‐alkyl complexes. While TMEDA is not bound to the catalytically active species, these active iron(0) complexes cannot be accessed in the absence of TMEDA. This mode of action, allowing for controlled reduction and access to iron(0) species, represents a new paradigm for the role of this important reaction additive in iron catalysis

Green and brown bridges between weeds and crops reveal novel Diaporthe species in Australia

Diaporthe (syn. Phomopsis) species are well-known saprobes, endophytes or pathogens on a range of plants. Several species have wide host ranges and multiple species may sometimes colonise the same host species. This study describes eight novel Diaporthe species isolated from live and/or dead tissue from the broad acre crops lupin, maize, mungbean, soybean and sunflower, and associated weed species in Queensland and New South Wales, as well as the environmental weed bitou bush (Chrysanthemoides monilifera subsp. rotundata) in eastern Australia. The new taxa are differentiated on the basis of morphology and DNA sequence analyses based on the nuclear ribosomal internal transcribed spacer region, and part of the translation elongation factor-1α and ß-tubulin genes. The possible agricultural significance of live weeds and crop residues ('green bridges') as well as dead weeds and crop residues ('brown bridges') in aiding survival of the newly described Diaporthe species is discussed

Further investment in Aboriginal and Torres Strait Islander men's health research funding is urgently required

Kootsy Canuto, Jacob Prehn, Karla Canuto, Rosie Neate, Graham Gee, Corey Kennedy, Celina Gaweda, Oliver Black, James Smith, Alex Brow

AVONET: Morphological, ecological and geographical data for all birds

Functional traits offer a rich quantitative framework for developing and testing theories in evolutionary biology, ecology and ecosystem science. However, the potential of functional traits to drive theoretical advances and refine models of global change can only be fully realised when species-level information is complete. Here we present the AVONET dataset containing comprehensive functional trait data for all birds, including six ecological variables, 11 continuous morphological traits, and information on range size and location. Raw morphological measurements are presented from 90,020 individuals of 11,009 extant bird species sampled from 181 countries. These data are also summarised as species averages in three taxonomic formats, allowing integration with a global phylogeny, geographical range maps, IUCN Red List data and the eBird citizen science database. The AVONET dataset provides the most detailed picture of continuous trait variation for any major radiation of organisms, offering a global template for testing hypotheses and exploring the evolutionary origins, structure and functioning of biodiversity.Fil: Tobias, Joseph A.. Imperial College London; Reino Unido. University of Oxford; Reino UnidoFil: Sheard, Catherine. University of Oxford; Reino Unido. University of Bristol; Reino UnidoFil: Pigot, Alex L.. University of Oxford; Reino Unido. University College London; Estados UnidosFil: Devenish, Adam J. M.. Imperial College London; Reino UnidoFil: Yang, Jingyi. Imperial College London; Reino UnidoFil: Sayol, Ferran. University College London; Estados UnidosFil: Neate Clegg, Montague H. C.. University of Oxford; Reino Unido. University of Utah; Estados UnidosFil: Alioravainen, Nico. University of Oxford; Reino Unido. Natural Resources Institute Finland; FinlandiaFil: Weeks, Thomas L.. Imperial College London; Reino Unido. Natural History Museum; Reino UnidoFil: Barber, Robert A.. Imperial College London; Reino UnidoFil: Walkden, Patrick A.. Imperial College London; Reino Unido. Natural History Museum; Reino UnidoFil: MacGregor, Hannah E. A.. University of Oxford; Reino Unido. University of Bristol; Reino UnidoFil: Jones, Samuel E. I.. University of Oxford; Reino Unido. University of London; Reino UnidoFil: Vincent, Claire. Organización de Las Naciones Unidas; ArgentinaFil: Phillips, Anna G.. Senckenberg Biodiversity And Climate Research Centre; AlemaniaFil: Marples, Nicola M.. Trinity College; Estados UnidosFil: Montaño Centellas, Flavia A.. Universidad Mayor de San Andrés; Bolivia. University of Florida; Estados UnidosFil: Leandro Silva, Victor. Universidade Federal de Pernambuco; BrasilFil: Claramunt, Santiago. University of Toronto; Canadá. Royal Ontario Museum; CanadáFil: Darski, Bianca. Universidade Federal do Rio Grande do Sul; BrasilFil: Freeman, Benjamin G.. University of British Columbia; CanadáFil: Bregman, Tom P.. University of Oxford; Reino Unido. Future-Fit Foundation; Reino UnidoFil: Cooney, Christopher R.. University Of Sheffield; Reino UnidoFil: Hughes, Emma C.. University Of Sheffield; Reino UnidoFil: Capp, Elliot J. R.. University Of Sheffield; Reino UnidoFil: Varley, Zoë K.. University Of Sheffield; Reino Unido. Natural History Museum; Reino UnidoFil: Friedman, Nicholas R.. Okinawa Institute of Science and Technology Graduate University; JapónFil: Korntheuer, Heiko. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Corrales Vargas, Andrea. Universidad Nacional de Costa Rica; Costa RicaFil: García, Natalia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentin

What Is the Evidence Base for Climate-Smart Agriculture in East and Southern Africa? A Systematic Map

More than 500 million USD will soon be invested in climate-smart agriculture (CSA) programmes in sub-Saharan Africa. Improving smallholder farm management is the core of most of these programmes. However, there has been no comprehensive information available to evaluate how changing agricultural practices increases food production, improves resilience of farming systems and livelihoods, and mitigates climate change—the goals of CSA. Here, we present a systematic map—an overview of the availability of scientific evidence—for CSA in five African countries: Tanzania, Malawi, Mozambique, Zimbabwe and Zambia. We conducted a systematic literature search of the effects of 102 technologies, including farm management practices (e.g., leguminous intercropped agroforestry, increased protein content of livestock diets, etc.), on 57 indicators consistent with CSA goals (e.g., yield, water use efficiency, carbon sequestration, etc.) as part of an effort called the "CSA Compendium". Our search of peer-reviewed articles in Web of Science and Scopus produced 150,567 candidate papers across developing countries in the global tropics. We screened titles, abstracts and full texts against predetermined inclusion criteria, for example that the investigation took place in a tropical developing country and contains primary data on how both a CSA practice and non-CSA control affect a preselected indicator. More than 1500 papers met these criteria from Africa, of which, 153 contained data collected in one of the five countries. Mapping the studies shows geographic and topical clustering in a few locations, around relatively few measures of CSA and for a limited number of commodities, indicating potential for skewed results and highlighting gaps in the evidence. This study sets the baseline for the availability of evidence to support CSA programming in the five countries

Mediterranean and MIND dietary patterns and cognitive performance in multiple sclerosis: A cross-sectional analysis of the UK Multiple Sclerosis Register

Background: Multiple sclerosis (MS) is a chronic auto-immune neuroinflammatory disorder presenting as a range of systemic and neurological symptoms, including cognitive impairment. Emerging evidence suggests that diets targeting brain health—such as the Mediterranean (MED) and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets—may improve cognitive function; however, studies examining their role in people living with MS are limited. Methods: We examined cross-sectional associations between diet and cognition data from 967 participants in the United Kingdom Multiple Sclerosis Register (UKMSR). Dietary pattern scores (alternate Mediterranean; aMED, and MIND) were derived from the 130-item EPIC-Norfolk food frequency questionnaire. Cognition was assessed using the MS-specific Cognitron-MS (C-MS) battery (13 tasks) and summarised as overall cognition (global G factor) and four domains (object memory, problem solving, information processing speed [IPS], and words memory). Cognitive outcomes were expressed as Deviation-from-Expected (DfE) scores standardised to demographic and device characteristics using external regression-based norms. Linear models were adjusted for total energy intake, MS phenotype, disease duration since diagnosis, and current disease-modifying therapy (DMT) use. Interactions tested moderation by MS phenotype (relapsing vs. progressive MS) and current DMT use (yes vs. no). Sensitivity analyses included within-domain multiple-comparison control, rank-based inverse-normal transformation, and winsorisation. Results: Greater alignment with aMED and MIND dietary patterns were associated with higher scores in specific cognitive domains but not in overall cognition. Higher aMED scores were associated most consistently with better IPS, while higher MIND scores were additionally associated with better words memory. In categorical models, participants in the middle or highest tertiles of aMED or MIND scores performed up to ~0.4 SD better on tasks of Verbal Analogies, Word Definitions, Simple Reaction Time, Words Memory Immediate, or Words Memory Delays compared with those in the lowest tertile. These findings were robust across sensitivity analyses. Stratified analyses showed differential cognitive performance and diet-cognition associations by MS phenotype and DMT use. Conclusions: Mediterranean and MIND dietary patterns showed modest cross-sectional associations with specific cognition domains, with differential cognitive performance in different subgroups according to MS phenotype and DMT use. Although causal inference is not possible, our findings indicate future MS-related dietary studies (longitudinal and/or randomised controlled trials) examining cognitive function domains across different MS subgroups are warranted