IMPORTANCE: The dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, moderate to severe atopic dermatitis (AD). OBJECTIVE: To assess the efficacy and safety of different dupilumab ...regimens in maintaining response after 16 weeks of initial treatment. DESIGN, SETTING, AND PARTICIPANTS: The Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (LIBERTY AD SOLO-CONTINUE) was a randomized, double-blind, phase 3 clinical trial conducted from March 25, 2015, to October 18, 2016, at 185 sites in North America, Europe, Asia, and Japan. Patients with moderate to severe AD who received dupilumab treatment and achieved an Investigator’s Global Assessment score of 0 or 1 or 75% improvement in Eczema Area and Severity Index scores (EASI-75) at week 16 in 2 previous dupilumab monotherapy trials (LIBERTY AD SOLO 1 and 2) were rerandomized in SOLO-CONTINUE. After completing SOLO-CONTINUE, patients were followed up for up to 12 weeks or enrolled in an open-label extension. Data were analyzed from December 5 to 12, 2016. INTERVENTIONS: High-responding patients treated with dupilumab in SOLO were rerandomized 2:1:1:1 to continue their original regimen of dupilumab, 300 mg, weekly or every 2 weeks or to receive dupilumab, 300 mg, every 4 or 8 weeks or placebo for 36 weeks. MAIN OUTCOMES AND MEASURES: Percentage change in EASI score from baseline during the SOLO-CONTINUE trial, percentage of patients with EASI-75 at week 36, and safety. RESULTS: Among the 422 patients (mean SD age, 38.2 14.5 years; 227 53.8% male), continuing dupilumab treatment once weekly or every 2 weeks maintained optimal efficacy, with negligible change in percent EASI improvement from SOLO 1 and 2 baseline during the SOLO-CONTINUE trial (−0.06%; P < .001 vs placebo); percent change with the other regimens dose-dependently worsened (dupilumab every 4 weeks, −3.84%; dupilumab every 8 weeks, −6.84%; placebo, −21.67%). More patients taking dupilumab weekly or every 2 weeks (116 of 162 71.6%; P < .001 vs placebo) maintained EASI-75 response than those taking dupilumab every 4 weeks (49 of 84 58.3%) or every 8 weeks (45 of 82 54.9%) or those taking placebo (24 of 79 30.4%). Overall adverse event incidences were 70.7% in the weekly or every 2 weeks group, 73.6% in the every 4 weeks group, 75.0% in the every 8 weeks group, and 81.7% in the placebo group. Treatment groups had similar conjunctivitis rates. Treatment-emergent antidrug antibody incidence was lower with more frequent dupilumab dose regimens (11.3% in the placebo group and 11.7%, 6.0%, 4.3%, and 1.2% in the dupilumab every 8 weeks, every 4 weeks, every 2 weeks, and weekly groups, respectively). CONCLUSIONS AND RELEVANCE: In this trial, continued response over time was most consistently maintained with dupilumab administered weekly or every 2 weeks. Longer dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of dupilumab every 2 weeks is recommended for long-term treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02395133
Trophic rewilding as a climate change mitigation strategy? Cromsigt, Joris P. G. M.; te Beest, Mariska; Kerley, Graham I. H. ...
Philosophical transactions - Royal Society. Biological sciences,
10/2018, Letnik:
373, Številka:
1761
Journal Article
Recenzirano
Odprti dostop
The loss of megafauna at the terminal Pleistocene has been linked to a wide range of Earth-system-level changes, such as altered greenhouse gas budgets, fire regimes and biome-level vegetation ...changes. Given these influences and feedbacks, might part of the solution for mitigating anthropogenic climate change lie in the restoration of extant megafauna to ecosystems? Here, we explore the potential role of trophic rewilding on Earth's climate system. We first provide a novel synthesis of the various ways that megafauna interact with the major drivers of anthropogenic climate change, including greenhouse gas storage and emission, aerosols and albedo. We then explore the role of rewilding as a mitigation tool at two scales: (i) current and near-future opportunities for national or regional climate change mitigation portfolios, and (ii) more radical opportunities at the global scale. Finally, we identify major knowledge gaps that complicate the complete characterization of rewilding as a climate change mitigation strategy. Our perspective is urgent since we are losing the Earth's last remaining megafauna, and with it a potential option to address climate change.
This article is part of the theme issue ‘Trophic rewilding: consequences for ecosystems under global change’.
Why are there more species in the tropics than in temperate regions? In recent years, this long‐standing question has been addressed primarily by seeking environmental correlates of diversity. But to ...understand the ultimate causes of diversity patterns, we must also examine the evolutionary and biogeographic processes that directly change species numbers (i.e., speciation, extinction, and dispersal). With this perspective, we dissect the latitudinal diversity gradient in hylid frogs. We reconstruct a phylogeny for 124 hylid species, estimate divergence times and diversification rates for major clades, reconstruct biogeographic changes, and use ecological niche modeling to identify climatic variables that potentially limit dispersal. We find that hylids originated in tropical South America and spread to temperate regions only recently (leaving limited time for speciation). There is a strong relationship between the species richness of each region and when that region was colonized but not between the latitudinal positions of clades and their rates of diversification. Temperature seasonality seemingly limits dispersal of many tropical clades into temperate regions and shows significant phylogenetic conservatism. Overall, our study illustrates how two general principles (niche conservatism and the time‐for‐speciation effect) may help explain the latitudinal diversity gradient as well as many other diversity patterns across taxa and regions.
Summary Background In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nucleoside reverse ...transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals. Methods In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV-1-infected adults (aged ≥18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. Patients and investigators were masked to doses of cabotegravir received for 96 weeks, but not to the assignment of cabotegravir or efavirenz. The primary endpoint was the proportion of patients with fewer than 50 copies per mL of HIV-1 RNA (US Food and Drug Administration snapshot algorithm) at week 48. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , NCT01641809. Findings Of 243 patients randomly allocated and treated, 156 (86%) of 181 patients in the cabotegravir groups (52 87% of 60, 51 85% of 60, and 53 87% of 61 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 46 (74%) of 62 in the efavirenz group had fewer than 50 copies per mL of HIV-1 RNA after induction therapy. After patients in the cabotegravir groups were changed over from dual NRTIs to rilpivirine at week 24, 149 (82%; 95% CI 77–88) patients in the cabotegravir groups (48 80%; 70–90, 48 80%; 70–90, and 53 87%; 78–95 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 44 (71%; 60–82) in the efavirenz group were virologically suppressed at week 48, and 137 (76%; 69–82) receiving cabotegravir (41 68%; 57–80, 45 75%; 64–86, and 51 84%; 74–93 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 39 (63%; 51–75) in the efavirenz group were virologically suppressed at week 96. Treatment-related adverse events were reported by 93 (51%) cabotegravir-treated patients (28 47%, 32 53%, and 33 54% patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 42 (68%) efavirenz-treated patients. Six (3%) patients in the cabotegravir groups (one 2%, one 2%, and four 7% patients in the 10 mg, 30 mg, and 60 mg groups, respectively) withdrew because of treatment-emergent adverse events compared with nine (15%) in the efavirenz group. Interpretation Cabotegravir plus dual NRTI therapy had potent antiviral activity during the induction phase. As a two-drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96. Combined efficacy and safety results lend support to our selection of oral cabotegravir 30 mg once a day for further assessment. LATTE precedes studies of the assessment of longacting injectable formulations of both drugs as a two-drug regimen for the treatment of HIV-1 infection. Funding ViiV Healthcare and Janssen Research and Development.
ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell ...growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.
Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, and the molecular etiology remains undiagnosed in the majority of cases. Through ...whole-exome sequencing, we identified recessive nonsense and splicing mutations in FBXL4 segregating in three unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis, and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that colocalizes with mitochondria and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals. Expression of the wild-type FBXL4 transcript in cell lines from two subjects fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together our data demonstrate that mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability.
Macroautophagy has been shown to be important for the cellular remodelling required for Leishmania differentiation. We now demonstrate that L. major contains a functional ATG12-ATG5 conjugation ...system, which is required for ATG8-dependent autophagosome formation. Nascent autophagosomes were found commonly associated with the mitochondrion. L. major mutants lacking ATG5 (Δatg5) were viable as promastigotes but were unable to form autophagosomes, had morphological abnormalities including a much reduced flagellum, were less able to differentiate and had greatly reduced virulence to macrophages and mice. Analyses of the lipid metabolome of Δatg5 revealed marked elevation of phosphatidylethanolamines (PE) in comparison to wild type parasites. The Δatg5 mutants also had increased mitochondrial mass but reduced mitochondrial membrane potential and higher levels of reactive oxygen species. These findings indicate that the lack of ATG5 and autophagy leads to perturbation of the phospholipid balance in the mitochondrion, possibly through ablation of membrane use and conjugation of mitochondrial PE to ATG8 for autophagosome biogenesis, resulting in a dysfunctional mitochondrion with impaired oxidative ability and energy generation. The overall result of this is reduced virulence.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Museum records have great potential to provide valuable insights into the vulnerability, historic distribution, and conservation of species, especially when coupled with species-distribution models ...used to predict species' ranges. Yet, the increasing dependence on species-distribution models in identifying conservation priorities calls for a more critical evaluation of model robustness. We used 11 bird species of conservation concern in Brazil's highly fragmented Atlantic Forest and data on environmental conditions in the region to predict species distributions. These predictions were repeated for five different model types for each of the 11 bird species. We then combined these species distributions for each model separately and applied a reserve-selection algorithm to identify priority sites. We compared the potential outcomes from the reserve selection among the models. Although similarity in identification of conservation reserve networks occurred among models, models differed markedly in geographic scope and flexibility of reserve networks. It is essential for planners to evaluate the conservation implications of false-positive and false-negative errors for their specific management scenario before beginning the modeling process. Reserve networks selected by models that minimized false-positive errors provided a better match with priority areas identified by specialists. Thus, we urge caution in the use of models that overestimate species' occurrences because they may misdirect conservation action. Our approach further demonstrates the great potential value of museum records to biodiversity studies and the utility of species-distribution models to conservation decision-making. Our results also demonstrate, however, that these models must be applied critically and cautiously.
Background Patients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not ...understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3DELAC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3.sup.WT/DELAC mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption. Methods We recorded sleep behavior in developing Shank3.sup.DELAC/DELAC, Shank3.sup.WT/DELAC, and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3.sup.WT/DELAC and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults. Results Male and female Shank3.sup.DELAC/DELAC mice slept significantly less than wild-type and Shank3.sup.WT/DELAC siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3.sup.WT/DELAC mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3.sup.WT/DELAC subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3.sup.WT/DELAC subjects had a significant reduction in risk aversion. CON Shank3.sup.WT/DELAC mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests. Limitations This study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3DELAC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities. Conclusion Our study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility. Keywords: Sleep, Autism spectrum disorder, Shank3, Social behavior, Brain development
Background "Financial toxicity" is a concern for patients, but little is known about how patients consider out-of-pocket cost in decisions. Sacubitril-valsartan provides a contemporary scenario to ...understand financial toxicity. It is guideline recommended for heart failure with reduced ejection fraction, yet out-of-pocket costs can be considerable. Methods and Results Structured interviews were conducted with 49 patients with heart failure with reduced ejection fraction at heart failure clinics and inpatient services. Patient opinions of the drug and its value were solicited after description of benefits using graphical displays. Descriptive quantitative analysis of closed-ended responses was conducted, and qualitative descriptive analysis of text data was performed. Of participants, 92% (45/49) said that they would definitely or probably switch to sacubitril-valsartan if their physician recommended it and out-of-pocket cost was $5 more per month than their current medication. Only 43% (21/49) would do so if out-of-pocket cost was $100 more per month ( P<0.001). At least 40% across all income categories would be unlikely to take sacubitril-valsartan at $100 more per month. Participants exhibited heterogeneous approaches to cost in decision making and varied on their use and interpretation of probabilistic information. Few (20%) participants stated physicians had initiated a conversation about cost in the past year. Conclusions Out-of-pocket cost variation reflective of contemporary cost sharing substantially influenced stated willingness to take sacubitril-valsartan, a guideline-recommended therapy with mortality benefit. These findings suggest a need for cost transparency to promote shared decision making. They also demonstrate the complexity of cost discussion and need to study how to incorporate out-of-pocket cost into clinical decisions.
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