Search

Artificial Intelligence (AI) is an emerging tool that could be leveraged to identify the effective conservation solutions demanded by the urgent biodiversity crisis. We present the results of our horizon scan of AI applications likely to significantly benefit biological conservation. An international panel of conservation scientists and AI experts identified 21 key ideas. These included species recognition to uncover 'dark diversity', multimodal models to improve biodiversity loss predictions, monitoring wildlife trade, and addressing human-wildlife conflict. We consider the potential negative impacts of AI adoption, such as AI colonialism and loss of essential conservation skills, and suggest how the conservation field might adapt to harness the benefits of AI while mitigating its risks., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Reformulation with addition of antioxidants is one potential mitigation strategy to prevent or reduce nitrosamine drug substance-related impurities (NDSRIs) in drug products. To explore whether there could be other approaches to demonstrate bioequivalence for a reformulated oral product, which typically needs in vivo bioequivalence studies to support the changes after approval, the effects of antioxidant on the in vitro permeability of BCS III model drug substances were investigated to see whether there could be any potential impact on drug absorption. Six antioxidants were screened and four (ascorbic acid, cysteine, α-tocopherol and propyl gallate) were selected based on their nitrosamine inhibition efficiencies. The study demonstrated that these four antioxidants, at the tested amounts, did not have observable impact on the in vitro permeability of the BCS III model drug substances across Caco-2 cell monolayers in the In Vitro Dissolution Absorption System (IDAS). An in vitro permeability study could be considered as part of one potential bioequivalence bridging approach for reformulated low-risk immediate release solid oral products and oral suspension products. Other factors such as the influence of antioxidants on intestinal transporter activities should be considered where appropriate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. All rights reserved.)

Objectives: The Siemens Point-of-Care Testing (POC) Atellica ® VTLi high-sensitivity troponin I (hsTnI) device has been previously validated. Verification independently provides evidence that an analytical procedure fulfils concordance with laboratory assays, imprecision, and hemolysis interference requirements., Methods: Five whole blood samples spanning the measuring interval were analysed 20 times in succession. Hemolysis interference was assessed at three troponin concentrations by spiking five hemolysate concentrations to plasma to achieve free hemoglobin concentrations 35-1,000 mg/dL. Concordance between whole blood (VTLi) and plasma on laboratory analysers (Beckman, Roche, Siemens) was assessed by Pearson correlation and kappa statistics at the (LOQ) and upper reference limit (URL). This was repeated for frozen plasma samples., Results: Coefficients of variation for whole blood were <10 % for whole blood troponin concentrations of 9.2 and 15.9 ng/L, thus below the URL. Hemolysis positively interfered; at 250 mg/dL affecting the low troponin sample (+3 ng/L; +60 %) and high troponin sample (+37 ng/L; +24 %). Correlation coefficients were 0.98, 0.90 and 0.97 between VTLi and Beckman, Roche and Siemens assays respectively. Corresponding kappa statistics were 0.80, 0.73 and 0.84 at the LOQ and 0.70, 0.44 and 0.67 at the URL., Conclusions: Concordances between VTLi and laboratory assays were at least non-inferior to those between laboratory assays. Imprecision met manufacturer claims and was consistent with a high sensitivity assay. There is potential for hemolysis interference, highlighting the need for quality samples. The results support performance characteristics previously reported in validation studies, and the device offers acceptable performance for use within intended medical settings., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Protected areas conserve biodiversity and ecosystem functions but might impede local economic growth. Understanding the global patterns and predictors of different relationships between protected area effectiveness and neighboring community economic growth can inform better implementation of the Kunming-Montreal Global Biodiversity Framework. We assessed 10,143 protected areas globally with matched samples to address the non-random location of protected areas. Our results show that protected areas resist human-induced land cover changes and do not limit nightlight increases in neighboring settlements. This result is robust, using different matching techniques, parameter settings, and selection of covariates. We identify four types of relationships between land cover changes and nightlight changes for each protected area: "synergy," "retreat," and two tradeoff relationships. About half of the protected areas (47.5%) retain their natural land cover and do so despite an increase of nightlights in the neighboring communities. This synergy relationship is the most common globally but varies between biomes and continents. Synergy is less frequent in the Amazon, Southeast Asia, and some developing areas, where most biodiversity resides and which suffer more from poverty. Smaller protected areas and those with better access to cities, moderate road density, and better baseline economic conditions have a higher probability of reaching synergy. Our results are promising, as the expansion of protected areas and increased species protection will rely more on conserving the human-modified landscape with smaller protected areas. Future interventions should address local development and biodiversity conservation together to achieve more co-benefits., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

For decades, China has implemented restoration programs on a large scale, thanks to its capacity to set policy and mobilize funding resources. An understanding of China's restoration achievements and remaining challenges will help to guide future efforts to restore 30% of its diverse ecosystems under the Kunming-Montreal Global Biodiversity Framework. Here we summarize the major transitions in China's approach to ecosystem restoration since the 1970s, with a focus on the underlying motivations for restoration, approaches to ecosystem management, and financing mechanisms. Whereas China's restoration efforts were predominantly guided by the delivery of certain ecosystem functions and services in earlier decades, more recently it has come to emphasize the restoration of biodiversity and ecosystem integrity. Accordingly, the focal ecosystems, approaches, and financing mechanisms of restoration have also been considerably diversified. This evolution is largely guided by the accumulation of scientific evidence and past experiences. We highlight the key challenges facing China's restoration efforts and propose future directions to improve restoration effectiveness, with regard to goal setting, monitoring, stakeholder involvement, adaptive management, resilience under climate change, and financing., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Familial hypercholesterolaemia (FH) variant positive subjects have over double the cardiovascular risk of low-density-lipoprotein-cholesterol (LDL-C) matched controls. It is desirable to optimise FH variant detection., Methods: We identified 213 subjects with FH gene panel reports ( LDLR , APOB , PCSK9 , and APOE ) based on total cholesterol >310 mg/dL; excluding triglycerides >400 mg/dL, cascade screening, and patients without pre-treatment LDL-C recorded. Demographic, clinical and lipid parameters were recorded., Results: A 31/213 (14.6%) patients had pathogenic or likely pathogenic FH variants. 10/213 (4.7%) had variants of uncertain significance. Compared with patients without FH variants, patients with FH variants were younger (median age, 39 years vs. 48 years), had more tendon xanthomata (25.0% vs. 11.4%), greater proportion of first degree relatives with total cholesterol >95th percentile (40.6% vs. 16.5%), higher LDL-C (median, 271 mg/dL vs. 236 mg/dL), and lower triglycerides (median, 115 mg/dL vs. 159 mg/dL). The Besseling et al. model (c-statistic 0.798) improved FH variant discrimination over Friedewald LDL-C (c-statistic 0.724), however, Dutch Lipid Clinic Network Score (DLCNS) did not (c-statistic 0.665). Sampson LDL-C (c-statistic 0.734) had similar discrimination to Friedewald., Conclusion: Although tendon xanthomata and first degree relatives with high total cholesterol >95th percentile were associated with FH variants, DLCNS or Simon Broome criteria did not improve FH detection over LDL-C. Sampson LDL-C did not significantly improve discrimination over Friedewald. Although lower triglycerides and younger age of presentation are positively associated with presence of FH variants, this information is not commonly used in FH detection algorithms apart from Besseling et al., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (Copyright © 2024 The Korean Society of Lipid and Atherosclerosis.)

The climbing mouse is a rare, small mammal listed as an endangered species on the China species red list. Molecular phylogenetic analyses and the evolutionary history of the genus remain unexplored because of the extreme difficulty in capturing individuals and their narrow distribution. Here, we collected 44 specimens, sequenced one mitochondrial and eight nuclear genes, and integrated morphological approaches to estimate phylogenetic relationships, delimit species boundaries, and explore evolutionary history. Molecular analyses and morphological results supported the validity of these four species. Here, we describe two new species, Vernaya meiguites sp. nov. and Vernaya nushanensis sp. nov., and recognize Vernaya foramena , previously considered a subspecies of Vernaya fulva , as a valid species. The estimated divergence time suggests that the climbing mouse began to diversify during the Pliocene (3.36 Ma)., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

In silico mechanistic modeling approaches have been designed by various stakeholders with the goal of supporting development and approval of generic orally inhaled drug products in the United States. This review summarizes the presentations and panel discussion that comprised a workshop session concentrated on the use of in silico models to predict various outcomes following orally inhaled drug product administration, including the status of such models and how model credibility may be effectively established., (© 2022 Teva Pharmaceuticals Ireland, Novartis Healthcare Private Limited, India and The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

On November 30, 2021, the US Food and Drug administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop titled "Establishing the Suitability of Model-Integrated Evidence (MIE) to Demonstrate Bioequivalence for Long-Acting Injectable and Implantable (LAI) Drug Products." This workshop brought relevant parties from the industry, academia, and the FDA in the field of modeling and simulation to explore, identify, and recommend best practices on utilizing MIE for bioequivalence (BE) assessment of LAI products. This report summerized presentations and panel discussions for topics including challenges and opportunities in development and assessment of generic LAI products, current status of utilizing MIE, recent research progress of utilizing MIE in generic LAI products, alternative designs for BE studies of LAI products, and model validation/verification strategies associated with different types of MIE approaches., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Regulatory science for generic dry powder inhalers (DPIs) in the United States (U.S.) has evolved over the last decade. In 2013, the U.S. Food and Drug Administration (FDA) published the draft product-specific guidance (PSG) for fluticasone propionate and salmeterol xinafoate inhalation powder. This was the first PSG for a DPI available in the U.S., which provided details on a weight-of-evidence approach for establishing bioequivalence (BE). A variety of research activities including in vivo and in vitro studies were used to support these recommendations, which have led to the first approval of a generic DPI in the U.S. for fluticasone propionate and salmeterol xinafoate inhalation powder in January of 2019. This review describes the scientific and regulatory activities that have been initiated by FDA to support the current BE recommendations for DPIs that led to the first generic DPI approvals, as well as research with novel in vitro and in silico methods that may potentially facilitate generic DPI development and approval., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Regulatory science for generic dry powder inhalation products worldwide has evolved over the last decade. The revised draft guidance Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - Quality Considerations [1] (Revision 1, April 2018) that FDA issued summarizes product considerations and potential critical quality attributes (CQAs). This guidance emphasizes the need to apply the principles of quality by design (QbD) and elements of pharmaceutical development discussed in the International Conference for Harmonisation of (ICH) guidelines. Research studies related to quality were used to support guidance recommendations, which preceded the first approval of a generic DPI product in the U.S. This review outlines scientific and regulatory hurdles that need to be surmounted to successfully bring a generic DPI to the market. The goal of this review focuses on relevant issues and various challenges pertaining to CMC topics of the generic DPI quality attributes. Furthermore, this review provides recommendations to abbreviated new drug application (ANDA) applicants to expedite generic approvals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Objectives: To describe a novel β-globin variant that interferes with HbA1c analysis by cation exchange HPLC., Design and Methods: Diabetes screening by HbA1c measurement was assessed using cation exchange HPLC and an immunoassay point-of-care analyzer. Routine hemoglobinopathy screening was performed including CBC, HbF and HbA 2 measurement by cation exchange HPLC and capillary electrophoresis (CE). Further variant characterization was undertaken by ESI TOF mass spectrometry and DNA sequencing., Results: Discordant HbA1c results were obtained for our subject, with elevated HbA1c of 52 mmol/mol measured by cation exchange HPLC and a normal level of 34 mmol/mol by immunoassay. Abnormal HbA1c peak shape prompted hemoglobinopathy screening to investigate potential variant interference. Cation exchange HPLC (using β-thalassemia program) and CE results were apparently normal, with HbF and HbA 2 detected within reference intervals. ESI TOF mass spectrometry revealed the presence of a variant β-globin chain. A novel missense variant was confirmed at codon 121 of the β-globin gene [β121 (GH4) Glu>Asp; HBB: c.366A>C], which we have named Hb Westport., Conclusions: Hb Westport is a novel β-globin variant that interferes with HbA1c measurement by Bio-Rad D-100 cation exchange HPLC, giving a falsely elevated result. This was clinically significant for our subject because the erroneously elevated HbA1c value was above the diabetes diagnostic threshold. Alternative methods for diabetes assessment should be considered in subjects with Hb Westport., (Copyright © 2022 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

The lives lost and economic costs of viral zoonotic pandemics have steadily increased over the past century. Prominent policymakers have promoted plans that argue the best ways to address future pandemic catastrophes should entail, "detecting and containing emerging zoonotic threats." In other words, we should take actions only after humans get sick. We sharply disagree. Humans have extensive contact with wildlife known to harbor vast numbers of viruses, many of which have not yet spilled into humans. We compute the annualized damages from emerging viral zoonoses. We explore three practical actions to minimize the impact of future pandemics: better surveillance of pathogen spillover and development of global databases of virus genomics and serology, better management of wildlife trade, and substantial reduction of deforestation. We find that these primary pandemic prevention actions cost less than 1/20th the value of lives lost each year to emerging viral zoonoses and have substantial cobenefits.

Natural disasters impose huge uncertainty and loss to human lives and economic activities. Landslides are one disaster that has become more prevalent because of anthropogenic disturbances, such as land-cover changes, land degradation, and expansion of infrastructure. These are further exacerbated by more extreme precipitation due to climate change, which is predicted to trigger more landslides and threaten sustainable development in vulnerable regions. Although biodiversity conservation and development are often regarded as having a trade-off relationship, here we present a global analysis of the area with co-benefits, where conservation through expanding protection and reducing deforestation can not only benefit biodiversity but also reduce landslide risks to human society. High overlap exists between landslide susceptibility and areas of endemism for mammals, birds, and amphibians, which are mostly concentrated in mountain regions. We identified 247 mountain ranges as areas with high vulnerability, having both exceptional biodiversity and landslide risks, accounting for 25.8% of the global mountainous areas. Another 31 biodiverse mountains are classified as future vulnerable mountains as they face increasing landslide risks because of predicted climate change and deforestation. None of these 278 mountains reach the Aichi Target 11 of 17% coverage by protected areas. Of the 278 mountains, 52 need immediate actions because of high vulnerability, severe threats from future deforestation and precipitation extremes, low protection, and high-population density and anthropogenic activities. These actions include protected area expansion, forest conservation, and restoration where it could be a cost-effective way to reduce the risks of landslides., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Accurate maps of species ranges are essential to inform conservation, but time-consuming to produce and update. Given the pace of change of knowledge about species distributions and shifts in ranges under climate change and land use, a need exists for timely mapping approaches that enable batch processing employing widely available data. We develop a systematic approach of batch-processing range maps and derived Area of Habitat maps for terrestrial bird species with published ranges below 125,000 km2 in Central and South America. (Area of Habitat is the habitat available to a species within its range.) We combine existing range maps with the rapidly expanding crowd-sourced eBird data of presences and absences from frequently surveyed locations, plus readily accessible, high resolution satellite data on forest cover and elevation to map the Area of Habitat available to each species. Users can interrogate the maps produced to see details of the observations that contributed to the ranges. Previous estimates of Areas of Habitat were constrained within the published ranges and thus were, by definition, smaller-typically about 30%. This reflects how little habitat within suitable elevation ranges exists within the published ranges. Our results show that on average, Areas of Habitat are 12% larger than published ranges, reflecting the often-considerable extent that eBird records expand the known distributions of species. Interestingly, there are substantial differences between threatened and non-threatened species. Some 40% of Critically Endangered, 43% of Endangered, and 55% of Vulnerable species have Areas of Habitat larger than their published ranges, compared with 31% for Near Threatened and Least Concern species. The important finding for conservation is that threatened species are generally more widespread than previously estimated., Competing Interests: The authors have declared that no competing interests exist. The views expressed in this publication do not necessarily reflect those of IUCN.

Habitat degradation and land-use change driven by the livestock sector are among the major causes of global biodiversity loss. Forests are crucial in maintaining biodiversity and mitigating climate change. Apart from continuing deforestation, forests also face increasing pressure from livestock grazing in the system, which is less understood compared to grasslands. Through a meta-analysis of 156 articles with 1936 data entries, this study assesses the effect of livestock on forest biodiversity, structure, and functions, varying with livestock types, livestock density, grazing history, and climatic factors. Our results show that livestock overall had a negative impact on the forest structure and functions, reduced species abundance but increased richness. Medium and large mammals, plant communities, and soil were more negatively affected compared to other groups such as birds and invertebrates. Livestock also influenced the role of forests in mitigating climate change. They changed forest carbon stock by reducing plant biomass; however, they did not significantly impact the soil carbon stock or soil greenhouse gas emissions. Ecosystem attributes were more affected in warmer and drier regions and by single species grazing than the mixed grazing. Past livestock grazing history moderates the impacts of livestock, with the strongest negative effect occurred with a history of 1-5 years. Nonetheless, livestock activities also had a positive impact on forest management, such as reducing forest flammability. Our results also indicate the lack of studies on how higher trophic levels respond to livestock disturbances and how grazing intensity moderates the effect, which includes grazing duration and livestock density. The complex responses of forests to livestock in different conditions call for more adaptive management depending on the conservation targets and evolution history., (© 2021 John Wiley & Sons Ltd.)

The COVID-19 pandemic is an alarm call to all on the risks of zoonotic diseases and the delicate relationship between nature and human health. In response, China has taken a proactive step by issuing a legal decision to ban consumption of terrestrial wildlife. However, concerns have been raised and opponents of bans argue that well-regulated trade should be promoted instead. By analyzing China's legal framework and management system regulating wildlife trade, together with state and provincial-level wildlife-trade licenses and wildlife criminal cases, we argue that current wildlife trade regulations do not function as expected. This is due to outdated protected species lists, insufficient cross-sector collaboration, and weak restrictions and law enforcement on farming and trading of species. The lack of quarantine standards for wildlife and increased wildlife farming in recent years pose great risks for food safety and public health. In addition, wildlife consumption is neither required for subsistence nor an essential part of Chinese diets. All these facts make the ban necessary to provoke improvement in wildlife management, such as updating protected species lists, revising laws and changing consumption behaviors. Nonetheless, the ban is not sufficient to address all the problems. To sustain the efficacy of the change, we propose that a long-term mechanism to reduce the demand and improve effective management is needed., (Copyright © 2020. Published by Elsevier Inc.)

How has the global network of protected areas developed - and which decisions have guided this development? Answering these questions may give insight into what might be possible in the next decade. In 2021, China will host the Convention of Biological Diversity's Conference, which will influence the coming decade's agenda. We consider how China expanded its protected areas in the last half-century. Did concerns about biodiversity protection drive those decisions, or were other factors responsible? Like other countries, China has protected remote places with few people that are unusually cold or dry or both. Despite that, species with small geographical ranges that have the highest risk of extinction are better protected than expected. Importantly, while the growth of total area and number of protected areas has slowed for the last decade, increases in protection of forested ecosystems and the species they contain have steadily increased. China's future reserve expansion must consider where to protect biodiversity, not just how much area to protect., (Copyright © 2020 Elsevier Inc. All rights reserved.)

International attention on the environmental impacts of China's Belt and Road Initiative (BRI) is increasing, but little is known internationally about the large corpus of Chinese BRI environmental research. We present the first systematic review of the Chinese and English-language BRI environmental research, supported with text mining and sentiment analysis. We found that the research is dominated by Chinese authors writing about BRI routes within China in Chinese, even though concerns around BRI are largely about impacts and benefits within host countries, and the volume of publications in English is recently catching up. Different disciplines and methods are well-represented across languages, apart from specific types of Chinese social science papers. The sentiments of academic research are largely neutral and less polarised than media discourse. We recommend that scientists and practitioners should pay more attention to BRI environmental impacts in developing countries and proactively engage local voices., Competing Interests: The authors have declared that no competing interests exist.

The Belt and Road Initiative (BRI) represents the largest infrastructure and development project in human history, and presents risks and opportunities for ecosystems, economies, and communities. Some risks (habitat fragmentation, roadkill) are obvious, however, many of the BRI's largest challenges for development and conservation are not obvious and require extensive consideration to identify. In this first BRI Horizon Scan, we identify 11 frontier issues that may have large environmental and social impacts but are not yet recognised. More generally, the BRI will increase China's participation in international environmental governance. Thus, new cooperative modes of governance are needed to balance geopolitical, societal, and environmental interests. Upgrading and standardising global environmental standards is essential to safeguard ecological systems and human societies., (Published by Elsevier Ltd.)

Protecting land to save biodiversity is a cornerstone of conservation. But how effective are protected areas? Two new studies on panda conservation reveal that protection is efficient and suggest ways for improving biodiversity protection., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The International Union for Conservation of Nature (IUCN) Red List of Threatened Species includes assessment of extinction risk for 98 512 species, plus documentation of their range, habitat, elevation, and other factors. These range, habitat and elevation data can be matched with terrestrial land cover and elevation datasets to map the species' area of habitat (AOH; also known as extent of suitable habitat; ESH). This differs from the two spatial metrics used for assessing extinction risk in the IUCN Red List criteria: extent of occurrence (EOO) and area of occupancy (AOO). AOH can guide conservation, for example, through targeting areas for field surveys, assessing proportions of species' habitat within protected areas, and monitoring habitat loss and fragmentation. We recommend that IUCN Red List assessments document AOH wherever practical., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

An 18-year-old male patient presented to our regional referral hospital postcollapse at home. This was about 48 hours following a 2 m fall from a mountain bike. CT scan at presentation showed a grade 3/4 laceration at the splenic lower pole with some haemoperitoneum. He was managed conservatively. However, on day 4 he developed increasing abdominal pain which prompted repeat CT abdominal angiography. This scan did not show any further active bleeding from the spleen, however, a coeliac artery dissection was discovered, which was not evident on the first scan. After liaison with the vascular surgery team at a tertiary hospital, this was treated conservatively. Coeliac artery dissection following blunt trauma is an extremely rare occurrence, with fewer than 10 cases described in the literature. To our knowledge, this is the first case of concurrent splenic injury and coeliac artery dissection following blunt trauma to be reported., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

In 2016, the US Food and Drug Administration (FDA) approved the first Abbreviated New Drug Application for Mometasone Furoate Nasal Suspension Spray. To establish the bioequivalence of this generic nasal suspension spray with the reference listed drug product (RLD), Nasonex®, a "weight-of-evidence" approach was utilized by the applicant that included formulation and device similarities, equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition to these testing for comprehensive evaluation of the drug product, FDA also considered supportive data generated by a novel in vitro method, Morphologically-Directed Raman Spectroscopy (MDRS), to characterize the particle size distribution (PSD) of active pharmaceutical ingredient (API) in the drug product. In this case, MDRS data eliminated the need for a comparative clinical endpoint bioequivalence study. The approval of the first generic Mometasone Furoate Nasal Suspension Spray is precedent-setting and paves a new pathway to establish bioequivalence for generic nasal suspension sprays. This approval also exemplifies FDA's commitment to advance regulatory science for evaluation of generic drug products.

It is theoretically possible to protect large fractions of species in relatively small regions. For plants, 85% of species occur entirely within just over a third of the Earth's land surface, carefully optimized to maximize the species captured. Well-known vertebrate taxa show similar patterns. Protecting half of Earth might not be necessary, but would it be sufficient given the current trends of protection? The predilection of national governments is to protect areas that are "wild," that is, typically remote, cold, or arid. Unfortunately, those areas often hold relatively few species. Wild places likely afford the easier opportunities for the future expansion of protected areas, with the expansion into human-dominated landscapes the greater challenge. We identify regions that are not currently protected, but that are wild, and consider which of them hold substantial numbers of especially small-ranged vertebrate species. We assess how successful the strategy of protecting the wilder half of Earth might be in conserving biodiversity. It is far from sufficient. (Protecting large wild places for reasons other than biodiversity protection, such as carbon sequestration and other ecosystem services, might still have importance.) Unexpectedly, we also show that, despite the bias in establishing large protected areas in wild places to date, numerous small protected areas are in biodiverse places. They at least partially protect significant fractions of especially small-ranged species. So, while a preoccupation with protecting large areas for the sake of getting half of Earth might achieve little for biodiversity, there is more progress in protecting high-biodiversity areas than currently appreciated. Continuing to prioritize the right parts of Earth, not just the total area protected, is what matters for biodiversity.

Oral modified-release (MR) products are dosage forms administered through the mouth and designed to release drug in a controlled manner to achieve maximum efficacy, minimal side effects, and better patient compliance. With significant progress in pharmaceutical technologies and favored therapeutic benefit, more and more oral MR products including the generic versions of these products are being developed, marketed, and used in the USA. Because different types of MR products may exhibit unique drug release modes and specific pharmacokinetic profiles, a better understanding of the regulation and evaluation of these generic MR products can help development and marketing of generic MR products that are therapeutically equivalent to the corresponding reference product. This review summarizes the general regulatory requirements for establishing bioequivalence between generic and reference oral MR products. In addition, some special regulatory considerations for bioequivalence evaluation are highlighted with examples of specific oral MR drug products.

The IUCN (International Union for Conservation of Nature) Red List classifies species according to their risk of extinction, informing global to local conservation decisions. Unfortunately, important geospatial data do not explicitly or efficiently enter this process. Rapid growth in the availability of remotely sensed observations provides fine-scale data on elevation and increasingly sophisticated characterizations of land cover and its changes. These data readily show that species are likely not present within many areas within the overall envelopes of their distributions. Additionally, global databases on protected areas inform how extensively ranges are protected. We selected 586 endemic and threatened forest bird species from six of the world's most biodiverse and threatened places (Atlantic Forest of Brazil, Central America, Western Andes of Colombia, Madagascar, Sumatra, and Southeast Asia). The Red List deems 18% of these species to be threatened (15 critically endangered, 29 endangered, and 64 vulnerable). Inevitably, after refining ranges by elevation and forest cover, ranges shrink. Do they do so consistently? For example, refined ranges of critically endangered species might reduce by (say) 50% but so might the ranges of endangered, vulnerable, and nonthreatened species. Critically, this is not the case. We find that 43% of species fall below the range threshold where comparable species are deemed threatened. Some 210 bird species belong in a higher-threat category than the current Red List placement, including 189 species that are currently deemed nonthreatened. Incorporating readily available spatial data substantially increases the numbers of species that should be considered at risk and alters priority areas for conservation.

The IUCN Red List has assessed the global distributions of the majority of the world's amphibians, birds and mammals. Yet these assessments lack explicit reference to widely available, remotely-sensed data that can sensibly inform a species' risk of extinction. Our first goal is to add additional quantitative data to the existing standardised process that IUCN employs. Secondly, we ask: do our results suggest species of concern-those at considerably greater risk than hitherto appreciated? Thirdly, these assessments are not only important on a species-by-species basis. By combining distributions of species of concern, we map conservation priorities. We ask to what degree these areas are currently protected and how might knowledge from remote sensing modify the priorities? Finally, we develop a quick and simple method to identify and modify the priority setting in a landscape where natural habitats are disappearing rapidly and so where conventional species' assessments might be too slow to respond. Tropical, mainland Southeast Asia is under exceptional threat, yet relatively poorly known. Here, additional quantitative measures may be particularly helpful. This region contains over 122, 183, and 214 endemic mammals, birds, and amphibians, respectively, of which the IUCN considers 37, 21, and 37 threatened. When corrected for the amount of remaining natural habitats within the known elevation preferences of species, the average sizes of species ranges shrink to <40% of their published ranges. Some 79 mammal, 49 bird, and 184 amphibian ranges are <20,000km2-an area at which IUCN considers most other species to be threatened. Moreover, these species are not better protected by the existing network of protected areas than are species that IUCN accepts as threatened. Simply, there appear to be considerably more species at risk than hitherto appreciated. Furthermore, incorporating remote sensing data showing where habitat loss is prevalent changes the locations of conservation priorities.

The giant panda attracts disproportionate conservation resources. How well does this emphasis protect other endemic species? Detailed data on geographical ranges are not available for plants or invertebrates, so we restrict our analyses to 3 vertebrate taxa: birds, mammals, and amphibians. There are gaps in their protection, and we recommend practical actions to fill them. We identified patterns of species richness, then identified which species are endemic to China, and then which, like the panda, live in forests. After refining each species' range by its known elevational range and remaining forest habitats as determined from remote sensing, we identified the top 5% richest areas as the centers of endemism. Southern mountains, especially the eastern Hengduan Mountains, were centers for all 3 taxa. Over 96% of the panda habitat overlapped the endemic centers. Thus, investing in almost any panda habitat will benefit many other endemics. Existing panda national nature reserves cover all but one of the endemic species that overlap with the panda's distribution. Of particular interest are 14 mammal, 20 bird, and 82 amphibian species that are inadequately protected. Most of these species the International Union for Conservation of Nature currently deems threatened. But 7 mammal, 3 bird, and 20 amphibian species are currently nonthreatened, yet their geographical ranges are <20,000 km(2) after accounting for elevational restriction and remaining habitats. These species concentrate mainly in Sichuan, Yunnan, Nan Mountains, and Hainan. There is a high concentration in the east Daxiang and Xiaoxiang Mountains of Sichuan, where pandas are absent and where there are no national nature reserves. The others concentrate in Yunnan, Nan Mountains, and Hainan. Here, 10 prefectures might establish new protected areas or upgrade local nature reserves to national status., (© 2015 Society for Conservation Biology.)

This article is part of a series of reports from the "Orlando Inhalation Conference-Approaches in International Regulation" which was held in March 2014, and coorganized by the University of Florida and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of the conference was to foster the exchange of ideas and knowledge across the global scientific and regulatory community in order to identify and help move towards strategies for internationally harmonized, science-based regulatory approaches for the development and marketing approval of inhalation medicines, including innovator and second entry products. This article provides an integrated perspective of case studies and discussion related to in vitro testing of orally inhaled products, including in vitro-in vivo correlations and requirements for in vitro data and statistical analysis that support quality or bioequivalence for regulatory applications.

International regulatory agencies have developed recommendations and guidances for bioequivalence approaches of orally inhaled drug products (OIDPs) for local action. The objective of this article is to discuss the similarities and differences among these approaches used by international regulatory authorities when applications of generic and/or subsequent entry locally acting OIDPs are evaluated. We focused on four jurisdictions that currently have published related guidances for generic and/or subsequent entry OIDPs. They are Therapeutic Goods Administration (TGA) in Australia, Health Canada (HC) in Canada, European Medicines Association (EMA) of European Union (EU), and the Food and Drug Administration (FDA) in the United States of America (USA). The comparisons of these bioequivalence (BE) recommendations are based on selection of reference products, formulation and inhaler device comparisons, and in vitro tests and in vivo studies, including pharmacokinetic (PK), pharmacodynamics (PD), and clinical studies. For the in vivo studies, the study design, choices of dose, subject inclusion/ exclusion criteria, study period, study endpoint, and equivalence criteria are elaborated in details. The bioequivalence on multiple-strength products and waiver options are also discussed.

Equivalence testing of aerodynamic particle size distribution (APSD) through multi-stage cascade impactors (CIs) is important for establishing bioequivalence of orally inhaled drug products. Recent work demonstrated that the median of the modified chi-square ratio statistic (MmCSRS) is a promising metric for APSD equivalence testing of test (T) and reference (R) products as it can be applied to a reduced number of CI sites that are more relevant for lung deposition. This metric is also less sensitive to the increased variability often observed for low-deposition sites. A method to establish critical values for the MmCSRS is described here. This method considers the variability of the R product by employing a reference variance scaling approach that allows definition of critical values as a function of the observed variability of the R product. A stepwise CI equivalence test is proposed that integrates the MmCSRS as a method for comparing the relative shapes of CI profiles and incorporates statistical tests for assessing equivalence of single actuation content and impactor sized mass. This stepwise CI equivalence test was applied to 55 published CI profile scenarios, which were classified as equivalent or inequivalent by members of the Product Quality Research Institute working group (PQRI WG). The results of the stepwise CI equivalence test using a 25% difference in MmCSRS as an acceptance criterion provided the best matching with those of the PQRI WG as decisions of both methods agreed in 75% of the 55 CI profile scenarios.

Establishing bioequivalence (BE) of drugs indicated to treat cancer poses special challenges. For ethical reasons, often, the studies need to be conducted in cancer patients rather than in healthy volunteers, especially when the drug is cytotoxic. The Biopharmaceutics Classification System (BCS) introduced by Amidon (1) and adopted by the FDA, presents opportunities to avoid conducting the bioequivalence studies in humans. This paper analyzes the application of the BCS approach by the generic pharmaceutical industry and the FDA to oncology drug products. To date, the FDA has granted BCS-based biowaivers for several drug products involving at least four different drug substances, used to treat cancer. Compared to in vivo BE studies, development of data to justify BCS waivers is considered somewhat easier, faster, and more cost effective. However, the FDA experience shows that the approval times for applications containing in vitro studies to support the BCS-based biowaivers are often as long as the applications containing in vivo BE studies, primarily because of inadequate information in the submissions. This paper deliberates some common causes for the delays in the approval of applications requesting BCS-based biowaivers for oncology drug products. Scientific considerations of conducting a non-BCS-based in vivo BE study for generic oncology drug products are also discussed. It is hoped that the information provided in our study would help the applicants to improve the quality of ANDA submissions in the future.

Demonstrating bioequivalence (BE) for nasal spray/aerosol products for local action has been very challenging because the relationship between the drug in systemic circulation and the drug reaching the nasal site of action has not been well established. Thus, the current BE standard for these drug/device combination products is based on a weight-of-evidence approach, which contains three major elements: equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition, formulation sameness and device similarity are evidences to support BE. This paper presents a comprehensive review of the scientific rationale of the current BE standard and their development history for nasal spray/aerosol products, as well as the Food and Drug Administration's review and approval status of generic nasal sprays/aerosols with the application of these BE standard.

Demonstration of equivalence in aerodynamic particle size distribution (APSD) is one key component for establishing bioequivalence of orally inhaled drug products. We previously proposed a modified version of the Chi-square ratio statistic (mCSRS) for APSD equivalence testing and demonstrated that the median of the distribution of the mCSRS (MmCSRS) is a robust metric when test (T) and reference (R) cascade impactor (CI) profiles are identical. Here, we systematically evaluate the behavior of the MmCSRS when T and R CI profiles differ from each other in their mean deposition and variability on a single and multiple sites. All CI profiles were generated by Monte-Carlo simulations based upon modified actual CI data. Twenty thousand sets of 30 T and 30 R CI profiles were simulated for each scenario, and the behavior of the MmCSRS was correlated to metrics that characterize the difference between T and R product in mean deposition and variability. The two key findings were, first, that the MmCSRS is more sensitive to difference between T and R CI profiles on high deposition sites, and second, that a cut-off value for APSD equivalence testing based on the MmCSRS needs to be scaled on the variability of the R product. The former is considered as beneficial for equivalence testing of CI profiles as it decreases the likelihood of failing identical CI profiles by chance, in part, due to increasing analytical variability associated with lower deposition sites. The latter is expected to be important for consistently being able to discriminate equivalent from inequivalent CI profiles.

"For-cause" inspections are initiated during the review of bioequivalence (BE) data submitted to Abbreviated New Drug Applications when possible scientific misconduct and study irregularities are discovered. We investigated the common reasons for initiating "for-cause" inspections related to the clinical, analytical, and dissolution study sites associated with BE studies. This information may help the pharmaceutical industry to understand the root causes of compliance failures in BE studies and help them to improve compliance with FDA's regulations, thereby facilitating more rapid approval of safe and effective generic drugs.

Dry powder inhalers (DPIs) are used to deliver locally acting drugs (e.g., bronchodilators and corticosteroids) for treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). Demonstrating bioequivalence (BE) for DPI products is challenging, primarily due to an incomplete understanding of the relevance of drug concentrations in blood or plasma to equivalence in drug delivery to the local site(s) of action. Thus, BE of these drug/device combination products is established based on an aggregate weight of evidence, which utilizes in vitro studies to demonstrate equivalence of in vitro performance, pharmacokinetic or pharmacodynamic studies to demonstrate equivalence of systemic exposure, and pharmacodynamic and clinical endpoint studies to demonstrate equivalence in local action. This review discusses key aspects of in vitro studies in supporting the establishment of BE for generic locally acting DPI products. These aspects include comparability in device resistance and equivalence in in vitro testing for single inhalation (actuation) content and aerodynamic particle size distribution.