Degradation of freshwater ecosystems and the services they provide is a primary cause of increasing water insecurity, raising the need for integrated solutions to freshwater management. While methods ...for characterizing the multi-faceted challenges of managing freshwater ecosystems abound, they tend to emphasize either social or ecological dimensions and fall short of being truly integrative. This paper suggests that management for sustainability of freshwater systems needs to consider the linkages between human water uses, freshwater ecosystems and governance. We present a conceptualization of freshwater resources as part of an integrated social-ecological system and propose a set of corresponding indicators to monitor freshwater ecosystem health and to highlight priorities for management. We demonstrate an application of this new framework —the Freshwater Health Index (FHI) — in the Dongjiang River Basin in southern China, where stakeholders are addressing multiple and conflicting freshwater demands. By combining empirical and modeled datasets with surveys to gauge stakeholders' preferences and elicit expert information about governance mechanisms, the FHI helps stakeholders understand the status of freshwater ecosystems in their basin, how ecosystems are being manipulated to enhance or decrease water-related services, and how well the existing water resource management regime is equipped to govern these dynamics over time. This framework helps to operationalize a truly integrated approach to water resource management by recognizing the interplay between governance, stakeholders, freshwater ecosystems and the services they provide.
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•A social-ecological framework is developed to assess freshwater health.•The framework links ecological, hydrological, and social parameters.•A set of indicators, the Freshwater Health Index, guides quantitative assessments.•The Index can be used to monitor changes or compare modeled scenarios to a baseline.
Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive ...impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial.
REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged ≥50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1·5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952.
Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5·4 (IQR 5·1–5·9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per 100 patient-years in people assigned placebo (hazard ratio HR 0·93, 95% CI 0·85–1·02; p=0·11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79–0·95; p=0·0018).
Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated.
Eli Lilly and Company.
This review provides a worked example of ‘best fit’ framework synthesis using the Theoretical Domains Framework (TDF) of health psychology theories as an a priori framework in the synthesis of ...qualitative evidence. Framework synthesis works best with ‘policy urgent’ questions.
The review question selected was: what are patients' experiences of prevention programmes for cardiovascular disease (CVD) and diabetes? The significance of these conditions is clear: CVD claims more deaths worldwide than any other; diabetes is a risk factor for CVD and leading cause of death.
A systematic review and framework synthesis were conducted. This novel method for synthesizing qualitative evidence aims to make health psychology theory accessible to implementation science and advance the application of qualitative research findings in evidence-based healthcare.
Findings from 14 original studies were coded deductively into the TDF and subsequently an inductive thematic analysis was conducted. Synthesized findings produced six themes relating to: knowledge, beliefs, cues to (in)action, social influences, role and identity, and context. A conceptual model was generated illustrating combinations of factors that produce cues to (in)action. This model demonstrated interrelationships between individual (beliefs and knowledge) and societal (social influences, role and identity, context) factors.
Several intervention points were highlighted where factors could be manipulated to produce favourable cues to action. However, a lack of transparency of behavioural components of published interventions needs to be corrected and further evaluations of acceptability in relation to patient experience are required. Further work is needed to test the comprehensiveness of the TDF as an a priori framework for ‘policy urgent’ questions using ‘best fit’ framework synthesis.
•Framework synthesis offers robust review methodology for ‘policy urgent’ questions.•The Theoretical Domains Framework combines constructs; more development work on its comprehensiveness is needed.•Qualitative research studies tell us about patient acceptability of prevention programmes.•Organisation and social context create distinctive professional-patient interaction.•Knowledge and beliefs about risk & symptoms combine to create cues to (in)action.
Spontaneous supratentorial intracerebral haemorrhage accounts for 20% of all stroke-related sudden neurological deficits, has the highest morbidity and mortality of all stroke, and the role of ...surgery remains controversial. We undertook a prospective randomised trial to compare early surgery with initial conservative treatment for patients with intracerebral haemorrhage.
A parallel-group trial design was used. Early surgery combined haematoma evacuation (within 24 h of randomisation) with medical treatment. Initial conservative treatment used medical treatment, although later evacuation was allowed if necessary. We used the eight-point Glasgow outcome scale obtained by postal questionnaires sent directly to patients at 6 months follow-up as the primary outcome measure. We divided the patients into good and poor prognosis groups on the basis of their clinical status at randomisation. For the good prognosis group, a favourable outcome was defined as good recovery or moderate disability on the Glasgow outcome scale. For the poor prognosis group, a favourable outcome also included the upper level of severe disability. Analysis was by intention to treat.
1033 patients from 83 centres in 27 countries were randomised to early surgery (503) or initial conservative treatment (530). At 6 months, 51 patients were lost to follow-up, and 17 were alive with unknown status. Of 468 patients randomised to early surgery, 122 (26%) had a favourable outcome compared with 118 (24%) of 496 randomised to initial conservative treatment (odds ratio 0.89 95% CI 0.66-1.19, p=0.414); absolute benefit 2.3% (-3.2 to 7.7), relative benefit 10% (-13 to 33).
Patients with spontaneous supratentorial intracerebral haemorrhage in neurosurgical units show no overall benefit from early surgery when compared with initial conservative treatment.
Dulaglutide (DU) 1.5 mg was associated with improved composite renal outcomes that included new-onset macroalbuminuria in people with type 2 diabetes with previous cardiovascular disease or ...cardiovascular risk factors in the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial. This exploratory post hoc analysis evaluated kidney function-related outcomes, excluding the new-onset macroalbuminuria component, among the REWIND participants.
Intent-to-treat analyses were performed on REWIND participants (n = 4,949 DU, n = 4,952 placebo). Time to occurrence of a composite kidney function-related outcome (≥40% sustained decline in estimated glomerular filtration rate eGFR, per the Chronic Kidney Disease Epidemiology Collaboration 2009 equation, end-stage renal disease, or renal-related death), and mean annual eGFR slope were examined. Analyses were conducted overall and within subgroups defined by baseline urinary albumin-to-creatinine ratio (UACR <30 or ≥30 mg/g) and baseline eGFR (<60 or ≥60 mL/min/1.73 m2).
The post hoc composite kidney function-related outcome occurred less frequently among participants assigned to DU than placebo (hazard ratio HR 0.75, 95% CI 0.62-0.92, P = 0.004), with no evidence of a differential DU treatment effect by UACR or eGFR subgroup. A ≥40% sustained eGFR decline occurred less frequently among participants assigned to DU than placebo (HR 0.72, 95% CI 0.58-0.88, P = 0.002). The mean annual decline in eGFR slope was significantly smaller for participants assigned to DU than placebo (-1.37 vs. -1.56 mL/min/1.73 m2/year, P < 0.001); results were similar for all subgroups.
The estimated 25% reduced hazard of a kidney function-related outcome among participants assigned to DU highlights its potential for delaying or slowing the development of diabetic kidney disease in people with type 2 diabetes.
The European Space Agency launched CryoSat-2 as the first European ice mission in 2010. Its advanced altimeter met primary objectives concerned with sea ice thickness and ice sheets. The value of ...Cryosat-2 data over global oceans was recognised, and operational products were developed via the CryoSat Ocean Processor (COP). The novel orbit of CryoSat-2 results in a denser coverage of sample points compared to other satellite altimeters. The National Oceanography Centre Sea Level Anomaly (NOCSLA) gridded product is based on interpolating Geophysical Ocean Products (GOP) using weights in space and time. GOP represents the highest quality operational ocean data. NOCSLA is a daily, ¼° sea level anomaly product covering non-coastal oceans between 60°N 60°S and January 2011 to October 2020. The paper presents the methodology and scientific applications of NOCSLA. Oceanographic features observed are compared against products from other missions, including Rossby waves and El Niño signals. Results show good agreement with other products, confirming the value of Cryosat-2 data for ocean science and applications.
The incidence of cutaneous melanoma has increased over the past several decades, making its early diagnosis a continuing public health priority. The ABCD (Asymmetry, Border irregularity, Color ...variegation, Diameter >6 mm) acronym for the appraisal of cutaneous pigmented lesions was devised in 1985 and has been widely adopted but requires reexamination in light of recent data regarding the existence of small-diameter (< or =6 mm) melanomas.
Cochrane Library and PubMed searches for the period 1980-2004 were conducted using search terms ABCD and melanoma and small-diameter melanoma. Bibliographies of retrieved articles were also used to identify additional relevant information.
Available data do not support the utility of lowering the diameter criterion of ABCD from the current greater than 6 mm guideline. However, the data support expansion to ABCDE to emphasize the significance of evolving pigmented lesions in the natural history of melanoma. Physicians and patients with nevi should be attentive to changes (evolving) of size, shape, symptoms (itching, tenderness), surface (especially bleeding), and shades of color.
The ABCD criteria for the gross inspection of pigmented skin lesions and early diagnosis of cutaneous melanoma should be expanded to ABCDE (to include "evolving"). No change to the existing diameter criterion is required at this time.
In participants with type 2 diabetes (T2D) in the REWIND trial, dulaglutide (DU) use for median follow-up of 5.4 years was associated with reduced composite renal outcomes, defined as the first ...occurrence of new macroalbuminuria, sustained decline in estimated glomerular filtration rate (eGFR) of ≥30%, or chronic renal replacement therapy. The objective of this post-hoc analysis was to evaluate the effect of dulaglutide on renal outcomes related to kidney function that are typically used in renal outcomes studies, defined as the composite endpoint of sustained eGFR decline ≥40%, end-stage renal disease (ESRD), or all-cause death. Participants with T2D at cardiovascular (CV) risk were randomized (1:1) to DU 1.5 mg once-weekly or placebo. This post-hoc analysis used Cox proportional hazards modeling for time to first event to determine the risk of renal outcomes. Sensitivity analyses were conducted by replacing the all-cause death component with CV or renal death, or renal death. At baseline, treatment groups had similar eGFR (mean±SD: DU=77.2±22.7; placebo=76.6±22.8). The incidence rate of the composite endpoint was significantly lower for the DU group compared with placebo (Table). Treatment with DU 1.5 mg was associated with a 17% risk reduction in kidney function-related outcomes, suggesting potential delay in progression of diabetic kidney disease in patients with T2D at CV risk.
Disclosure
J.E. Shaw: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mylan, Sanofi. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Eli Lilly and Company, Mylan. F.T. Botros: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Malik: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C. Atisso: Employee; Self; Eli Lilly and Company. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi.
Funding
Eli Lilly and Company
Neutrophil lifespan and function are regulated by hypoxia via components of the hypoxia inducible factor (HIF)/von Hippel Lindau/hydroxylase pathway, including specific roles for HIF-1α and prolyl ...hydroxylase-3. HIF-2α has both distinct and overlapping biological roles with HIF-1α and has not previously been studied in the context of neutrophil biology. We investigated the role of HIF-2α in regulating key neutrophil functions. Human and murine peripheral blood neutrophils expressed HIF-2α, with expression up-regulated by acute and chronic inflammatory stimuli and in disease-associated inflammatory neutrophil. HIF2A gain-of-function mutations resulted in a reduction in neutrophil apoptosis both ex vivo, through the study of patient cells, and in vivo in a zebrafish tail injury model. In contrast, HIF-2α–deficient murine inflammatory neutrophils displayed increased sensitivity to nitrosative stress induced apoptosis ex vivo and increased neutrophil apoptosis in vivo, resulting in a reduction in neutrophilic inflammation and reduced tissue injury. Expression of HIF-2α was temporally dissociated from HIF-1α in vivo and predominated in the resolution phase of inflammation. These data support a critical and selective role for HIF-2α in persistence of neutrophilic inflammation and provide a platform to dissect the therapeutic utility of targeting HIF-2α in chronic inflammatory diseases.
•Neutrophil lifespan is extended in patients with gain-of-function HIF2A mutations.•HIF-2α regulates in vivo neutrophil longevity and thus tissue inflammation and repair.
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