Community-managed conservation efforts at Tsingy Mahaloka/KOFAMA, northern Madagascar: Right place at the wrong time?

This paper provides a retrospective account of efforts, from 2007 to 2013, to establish a community-managed protected area just south of Ankarana National Park that would encompass the limestone massif known locally as Tsingy Mahaloka and adjacent remnant forest patches. Community members of the rural commune of Antsiravibe came together in 2007 and, with support from the Peace Corps, formed KOFAMA (Koperativa Fikambanana Ankarabe Mitsinjo Arivo) to oversee management of the Tsingy Mahaloka site. When KOFAMA was initially established, Tsingy Mahaloka was envisioned as an ecotourist destination. Ecotourism is a pillar of the new IUCN “Lemurs of Madagascar” conservation action plan (2013–2016), and can allow rural communities to (i) secure revenue for habitat protection; (ii) create economic incentives and benefits for residents; and, (iii) facilitate locally-supported conservation efforts. Ecotourism to Tsingy Mahaloka was seen as a means for future sustainable development in the area. KOFAMA, as the local organization to be responsible for management of the protected area, was intended to operate by a “bottom-up” approach, where local stakeholders take active participation and leadership in decision-making affecting the protected area. But, obviously, an ecotourist site needs tourists; this has proven to be a problem for KOFAMA and the Tsingy Mahaloka site. The Tsingy Mahaloka site, on the face of it, would appear to offer much that would attract and educate ecotourists, including: striking topography (the massif’s sheer limestone cliffs rising 80–100 metres above a flat coastal plain), a diverse endemic avifauna, a resident crowned lemur population, and extensive caves containing human burials made over generations. However, the site’s relatively remote location and Madagascar’s recent political crisis have worked against Tsingy Mahaloka becoming established as a site that ecotourists regularly visit. Regardless, a core group of local residents remain committed to the project’s original goals. At this point in KOFAMA’s history, however, an initial assessment of the organization draws attention to the limits of a “build it and they will come” approach to ecotourism, sustainable development, and locally-managed conservation efforts. The struggles encountered by KOFAMA in its efforts to oversee the Tsingy Mahaloka site highlight the importance of detailed ethnographic and socioeconomic work prior to embarking on such locally-managed conservation efforts. Le présent compte rendu porte sur une rétrospective des efforts déployés de 2007 à 2013 pour établir une aire protégée au sud du Parc National de l’Ankarana et qui concerne le massif calcaire du Tsingy Mahaloka ainsi que ce qu’il reste de forêt sur sa périphérie. En 2007, les membres de la communauté de la commune rurale d’Antsiravibe se sont organisés avec le soutien des volontaires du Corps de la Paix pour former le KOFAMA (Koperativa Fikambanana Ankarabe Mitsinjo Arivo) afin de superviser le site du Tsingy Mahaloka reconnu comme une aire à protéger par la communauté. Lorsque KOFAMA a été initialement établi, le Tsingy Mahaloka avait été retenu comme une destination écotouristique. L’écotourisme est d’ailleurs un pilier du nouveau plan d’action de conservation des lémuriens de Madagascar de l’UICN pour la période 2013–2016. L’écotourisme est ainsi proposé aux communautés rurales de la périphérie des aires protégées comme un moyen de sécuriser des revenus en échange de la protection de l’habitat, mais aussi un moyen de proposer des incitations économiques et des avantages pour les résidents, et enfin une structure destinée à faciliter les efforts de conservation qui sont supportés localement. L’écotourisme lié au Tsingy Mahaloka a été considéré comme une activité de développement durable qui s’inscrit dans l’avenir de la région. KOFAMA, en tant qu’organisation locale responsable de la gestion de l’aire protégée est destiné à fonctionner selon une approche de bas en haut dans laquelle les acteurs locaux s’engagent réellement et dirigent les prises de décisions affectant l’aire protégée. Mais, de toute évidence, le processus a besoin de touristes, ce qui a constitué un problème pour KOFAMA et le Tsingy Mahaloka. À première vue, le Tsingy Mahaloka semble offrir de nombreuses caractéristiques propres à attirer et éduquer des écotouristes, dont une topographie remarquable avec des falaises calcaires abruptes de 80-100 mètres de haut dominant une plaine côtière, une avifaune endémique variée, une population résidente de Lémurs couronnés et des grottes abritant des sépultures humaines déposées par plusieurs générations. Mais, non seulement le Tsingy Mahaloka est-il relativement isolé, mais la crise politique de 2009 à 2014 Madagascar a également joué contre le développement de l’écotourisme. Malgré cela, un groupe de gens motivés poursuit les premiers objectifs du projet. À ce stade de l’histoire de KOFAMA, une évaluation initiale de l’organisation montre les limites d’une approche du type « proposons quelque chose, ils viendront voir » aussi bien pour l’écotourisme, le développement durable que les efforts déployés localement pour la protection de la nature. Les problèmes rencontrés par KOFAMA dans ses efforts pour protéger le Tsingy Mahaloka soulignent l’importance de mener un travail ethnographique et socio-économique détaillé avant d’embarquer dans des efforts de protection de la nature gérés localement

Simple, Fast and Accurate Implementation of the Diffusion Approximation Algorithm for Stochastic Ion Channels with Multiple States

The phenomena that emerge from the interaction of the stochastic opening and closing of ion channels (channel noise) with the non-linear neural dynamics are essential to our understanding of the operation of the nervous system. The effects that channel noise can have on neural dynamics are generally studied using numerical simulations of stochastic models. Algorithms based on discrete Markov Chains (MC) seem to be the most reliable and trustworthy, but even optimized algorithms come with a non-negligible computational cost. Diffusion Approximation (DA) methods use Stochastic Differential Equations (SDE) to approximate the behavior of a number of MCs, considerably speeding up simulation times. However, model comparisons have suggested that DA methods did not lead to the same results as in MC modeling in terms of channel noise statistics and effects on excitability. Recently, it was shown that the difference arose because MCs were modeled with coupled activation subunits, while the DA was modeled using uncoupled activation subunits. Implementations of DA with coupled subunits, in the context of a specific kinetic scheme, yielded similar results to MC. However, it remained unclear how to generalize these implementations to different kinetic schemes, or whether they were faster than MC algorithms. Additionally, a steady state approximation was used for the stochastic terms, which, as we show here, can introduce significant inaccuracies. We derived the SDE explicitly for any given ion channel kinetic scheme. The resulting generic equations were surprisingly simple and interpretable - allowing an easy and efficient DA implementation. The algorithm was tested in a voltage clamp simulation and in two different current clamp simulations, yielding the same results as MC modeling. Also, the simulation efficiency of this DA method demonstrated considerable superiority over MC methods.Comment: 32 text pages, 10 figures, 1 supplementary text + figur

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Moonstruck Primates: Owl Monkeys (Aotus) Need Moonlight for Nocturnal Activity in Their Natural Environment

Primates show activity patterns ranging from nocturnality to diurnality, with a few species showing activity both during day and night. Among anthropoids (monkeys, apes and humans), nocturnality is only present in the Central and South American owl monkey genus Aotus. Unlike other tropical Aotus species, the Azara's owl monkeys (A. azarai) of the subtropics have switched their activity pattern from strict nocturnality to one that also includes regular diurnal activity. Harsher climate, food availability, and the lack of predators or diurnal competitors, have all been proposed as factors favoring evolutionary switches in primate activity patterns. However, the observational nature of most field studies has limited an understanding of the mechanisms responsible for this switch in activity patterns. The goal of our study was to evaluate the hypothesis that masking, namely the stimulatory and/or inhibitory/disinhibitory effects of environmental factors on synchronized circadian locomotor activity, is a key determinant of the unusual activity pattern of Azara's owl monkeys. We use continuous long-term (6–18 months) 5-min-binned activity records obtained with actimeter collars fitted to wild owl monkeys (n = 10 individuals) to show that this different pattern results from strong masking of activity by the inhibiting and enhancing effects of ambient luminance and temperature. Conclusive evidence for the direct masking effect of light is provided by data showing that locomotor activity was almost completely inhibited when moonlight was shadowed during three lunar eclipses. Temperature also negatively masked locomotor activity, and this masking was manifested even under optimal light conditions. Our results highlight the importance of the masking of circadian rhythmicity as a determinant of nocturnality in wild owl monkeys and suggest that the stimulatory effects of dim light in nocturnal primates may have been selected as an adaptive response to moonlight. Furthermore, our data indicate that changes in sensitivity to specific environmental stimuli may have been an essential key for evolutionary switches between diurnal and nocturnal habits in primates

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Long-term risk stratification for survivors of acute coronary syndromes. Results from the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study. LIPID Study Investigators.

OBJECTIVES: We developed a prognostic strategy for quantifying the long-term risk of coronary heart disease (CHD) events in survivors of acute coronary syndromes (ACS). BACKGROUND: Strategies for quantifying long-term risk of CHD events have generally been confined to primary prevention settings. The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, which demonstrated that pravastatin reduces CHD events in ACS survivors with a broad range of cholesterol levels, enabled assessment of long-term prognosis in a secondary prevention setting. METHODS: Based on outcomes in 8,557 patients in the LIPID study, a multivariate risk factor model was developed for prediction of CHD death or nonfatal myocardial infarction. Prognostic indexes were developed based on the model, and low-, medium-, high- and very high-risk groups were defined by categorizing the prognostic indexes. RESULTS: In addition to pravastatin treatment, the independently significant risk factors included: total and high density lipoprotein cholesterol, age, gender, smoking status, qualifying ACS, prior coronary revascularization, diabetes mellitus, hypertension and prior stroke. Pravastatin reduced coronary event rates in each risk level, and the relative risk reduction did not vary significantly between risk levels. The predicted five-year coronary event rates ranged from 5% to 19% for those assigned pravastatin and from 6.4% to 23.6% for those assigned placebo. CONCLUSIONS: Long-term prognosis of ACS survivors varied substantially according to conventional risk factor profile. Pravastatin reduced coronary risk within all risk levels; however, absolute risk remained high in treated patients with unfavorable profiles. Our risk stratification strategy enables identification of ACS survivors who remain at very high risk despite statin therapy