Eremophila genus to provide new knowledge on the presence of natural products and their bioactivities using polypharmocological screens. Sesquiterpenoids, diterpenoids and dimers of branched‐chain fatty acids with previously unknown chemical structures were identified. The collection of plant material from the Eremophila genus was carried out according to a ‘bioprospecting agreement’ with the Government of Western Australia. We recognize that several Eremophila species hold immense cultural significance to Australia's First Peoples. In spite of our best intentions to ensure that new knowledge gained about the genus Eremophila and any potential future benefits are shared in an equitable manner, in accordance with the Nagoya Protocol, we encounter serious dilemmas and potential conflicts in making benefit sharing with Australia's First Peoples a reality.In a cross‐continental research initiative, including researchers working in Australia and Denmark, and based on joint external funding by a 3‐year grant from the Novo Nordisk Foundation, we have used DNA sequencing, extensive chemical profiling and molecular networking analyses across the entire  Eremophilas are culturally important plants for many of Australia's First Peoples, and several species are recognized as important sources of traditional medicines, as also supported by a chemo‐evolutionary study across the entire genus. In this Perspectives review article, we outline dilemmas in achieving benefit sharing with Australia's First Peoples. Eremophila at the DNA and phytochemical levels; (ii) to identify natural products with unique chemical structures; (iii) to ascertain the potential of such natural products as lead compounds for the development of new pharmaceuticals; and (iv) to elucidate the biosynthetic routes for a selected set of natural products as the basis for bioproduction in heterologous hosts. In this Perspectives review article, we provide a short account of the results obtained and outline the research set‐up that made the study possible, including obtaining a ‘bioprospecting agreement’ in Western Australia and the challenges of ensuring that any potential future benefits developed from Eremophila can be shared in an equitable manner, in accordance with the Nagoya Protocol. It is important to recognize that many Eremophila species hold immense cultural significance to Australia's First Peoples, the Aboriginal Peoples.Eremophilas are culturally important plants for many of Australia's First Peoples, and several species are recognized as important sources of traditional medicines. Previous investigations of the chemical nature of their bioactive constituents were limited to a small number of species  is a large and diverse genus of plants endemic to mainland Australia , Wise Owl Consulting, Como, Western Australia: Bevan Buirchell is an Australian biological scientist with a cross disciplinary expertise in botany, biochemistry and plant genetics with a long career as a Plant Breeder with the Government of Western Australia and a special focus on lupin breeding , Rachael Fowler (ORCID: 0000‐0002‐8953‐7036), School of Biosciences, University of Melbourne, Australia: Mike Bayly, Rachael Fowler and their research group use DNA data to study the evolution, diversity and classification of the Australian flora including large and iconic plant groups such as eucalypts , now recognized as Eremophila , Louise Kjærulff (ORCID: 0000‐0001‐6274‐4265); Yong Zhao (ORCID: 0000‐0002‐0423‐5232); Hans Albert Pedersen (ORCID: 0000‐0003‐2289‐7384), Malene J. Petersen (ORCID: 0000‐0002‐0531‐8531); Line Fentz Rasmussen (ORCID: 0000‐0003‐0842‐6770); Emilie Kold Bredahl (ORCID: 000‐0002‐3709‐3779), Department of Drug Design and Pharmacology, University of Copenhagen: Dan Stærk is heading the Natural Products Research group and the Copenhagen Small‐Molecule NMR Center. He and his research group have discovered and structurally characterized a wealth of small‐molecule natural products from sources like medicinal plants, insects, marine organisms, microorganisms and food by‐products , Oliver Gericke (ORCID: 0000‐0002‐8638‐6797), Allison Maree Heskes (ORCID: 0000‐0002‐2732‐5185), Nikolaj Lervad Hansen (ORCID: 0000‐0002‐5938‐16591), Gustav Blichfeldt Pedersen (ORCID: 0000‐0002‐7830‐718X), Plant Biochemistry Laboratory, University of Copenhagen: Birger Lindberg Møller is a plant biochemist specializing in the biosynthesis and function of plant natural products, metabolomics, metabolic engineering and environmentally benign production of natural products using heterologous hosts   and Chi P. Ndi (ORCID: 0000‐0003‐4198‐3237), Quality Use of Medicines and Pharmacy Research Centre, University of South Australia: Susan Semple's group has a strong background in pharmacy and natural products and has published widely on Australian medicinal plants including Eremophila. A specific focus area of the research group has been identification of natural products and derivatives used in treatment of infections caused by multi‐drug resistant bacteria with inhibitors of bacterial efflux pumps being key targets  and by the Government of the Australian state of Queensland , Laura Mikél McNair (ORCID: 0000‐0002‐5213‐9931), Department of Neuroscience, University of Copenhagen: Claus Loland is an expert on the molecular pharmacology of membrane transporters with focus on the neurotransmitter:sodium symporter (NSS) class of proteins. The binding of ligands and the molecular mechanisms, which mediate the transport of substrates across the cell membrane are elucidated at atomic level resolution . It was specified how voucher specimens should be processed and deposited at the Western Australian Herbarium  for incorporation into the collection. The identification of new Eremophila taxa was to be reported to the Herbarium Curator. Eremophila species listed as ‘Declared Rare Flora’ were exempt from any collection. In 2020, the time frame of the bioprospecting agreement was renegotiated and, as a result, extended to 2027 and expanded to include the collection of root samples. The fees paid to the Department of Parks and Wildlife for each sample collected have been used for flora research.In 2017, the Department of Parks and Wildlife within the Western Australian Government was approached to negotiate and obtain a license agreement to collect Eremophila expeditions covering more than 80 000 km, mainly across the Western Australian arid zone   spectroscopy, identified a large number of sesquiterpenoids and diterpenoids and numerous flavonoids ‐furanone‐type in Eremophila bignoniiflora  Figure  (Gericke) Figure . The com) Figure . Clear p) Figure  (Gericke) Figure . Based os Figure  ‐furanone‐type sesquiterpenoids with PTP1B inhibitory activity , i.e. five hitherto unreported monomers and 10 hitherto unreported dimers, originating from head‐to‐tail or head‐to‐head Diels–Alder reactions of monomeric BCFAs . For the determination of the absolute stereochemistry, chiroptical methods are needed. Thus, for selected serrulatanes, electronic circular dichroism (ECD) spectra were acquired, and theoretical ECD spectra were calculated by time‐dependent density‐functional theory calculations. This showed a conserved 1Eremophila samples was immediately sent to Susan Semple's group for initial extracts to be prepared and subfractionated for the analysis of extracts and compounds with inhibitory effects against Enterobacteriaceae, Pseudomonas spp., Acinetobacter baumannii and multidrug‐resistant Staphylococcus aureus and the efflux pump systems of some of these bacteria  family of proteins. Of special interest was a set of unique branched‐chain fatty acid dimers isolated from E. oppositifolia that possess a pharmacological signature that has not been observed previously for any of these types of transporters. These effects have the potential to provide completely new therapeutic perspectives, such as alleviating the psychotic symptoms of patients with schizophrenia without having the severe side effects of the current antipsychotics. The research to substantiate this function and elucidate the molecular mechanism behind the novel pharmacological signature is being given high priority. From previous experiments, it is known that cocaine and cocaine‐like compounds induce an outward‐facing open conformation of the dopamine transporter (DAT) ‐cembratrien‐15‐ol and 5‐hydroxyviscidane, respectively , to form the observed products  capable of making NNPP were identified in each species  was also attempted, but was unsuccessful because of endogenous glucosyltransferase activity in the host plant, which caused glucosylation of the intermediates formed, thus preventing them from functioning as substrates for subsequent reactions. These circumstances blocked our planned heterologous production of cisoid‐diterpenoids in yeast and tobacco, and also prevented us from using this system for the functional characterization of P450 candidate genes. These experimental setbacks prevented us from establishing small‐scale production in yeast of cisoid‐diterpenoids with interesting medical properties, which could have formed the basis for patenting.A major challenge in this part of the project was engineering the diterpenoid pathways into a production host. In other research projects, we have been highly successful in elucidating the full pathways for structurally complex Eremophila diterpenoid biosynthesis during this project, the identification of the initial biosynthetic steps towards three major diterpene backbones, as well as the identification of candidate genes for the cytochrome P450 enzymes catalyzing further oxygenation reactions, provide a guide for the elucidation of the full biosynthetic routes. Likewise, the enzyme systems are now available to provide scaffolds for further modification and bioactivity testing. This will open up the possibility of biotechnological production  , based on specific agreed‐upon conditions. In our case, this included a way of sharing any future benefits, such as profits from the commercialization of plant compounds, with Aboriginal Peoples who could claim custodianship of the plants or knowledge associated with them, as stipulated in the Nagoya Protocol.As a team of natural scientists wishing to study Eremophila species to Aboriginal Peoples, we faced several challenges, most of which were related to our desire to investigate the presence of bioactive natural products and chemo‐evolutionary relationships across the entire Eremophila genus, instead of in a single or a few species. Accordingly, processes to identify the appropriate Aboriginal Custodians of each Eremophila species were not available. Records of accumulated knowledge within the many different groupings of First Nations Peoples of Australia associated with each of all these Eremophila species were also scarce. Some of the complexities that we faced were as follows: • The Indigenous Peoples of Australia  are many different and distinct groups, with their own cultures, customs, languages and laws. The different nations, language and social groups have been illustrated in the Australian Institute of Aboriginal and Torres Strait Islander Studies (AIATSIS) map of Indigenous Australia . Thanks to extensive prior communications from the organizing committee involving both Australians and Danes to establish the foundation for a fruitful meeting, the conference provided space for a multi‐stakeholder sensitive dialog on cultural differences, ownership of the land and plants, and future perspectives. Strong statements and subsequent discussions were essential for helping participants understand the ethical and scientific issues from different perspectives .We hope that the issues and limitations raised here can add to conversations among stakeholders, including First Nations Peoples and organizations, the plant sciences research community, lawyers and governments, examining how regulatory systems can be extended to improve benefit sharing in large studies including entire plant families or genera that include species used by First Nations Peoples. In this context, and as outlined in the original proposal to the Novo Nordisk Foundation, we took the opportunity to organize the ‘First Cross‐Continental After we signed the bioprospecting agreement in 2017, a number of proactive bottom‐up initiatives have been taken to invigorate the Nagoya Protocol and the principle of benefit sharing by creating space for Indigenous communities to provide their perspectives, including their own definitions and aspirations associated with access and benefit sharing Figure . We recoEremophila and the presence of bioactive natural products and their biosynthesis, and more papers are in the pipeline.In natural science, a key criterion for success and continued funding is to publish the results obtained in high‐impact journals. This parameter significantly affects our opportunities for continued funding. As outlined above, such criteria pose serious dilemmas and potential conflicts when the research carried out is highly cross‐disciplinary Figure . In direEremophila. We managed to bring together researchers with the desired competences to advance such an interdisciplinary research project. Key success criteria included willingness and ability to collaborate, mutual trust and dedication towards fulfilling the aims. The result was the integration of a comprehensive phylogeny of Eremophila based on DNA sequencing with extensive chemical profiling data to provide a chemo‐evolutionary perspective on this large genus (Figure Eremophila species, and to pinpoint which species or groups of species should be the focus of future research on identifying new natural products.As outlined above, all researchers involved in the 3‐year research initiative ‘Desert‐Loving Therapeutics’ funded with 2.0 million Euro by the Novo Nordisk Foundation Interdisciplinary Synergy program were successful in providing new knowledge on the Australian genus Eremophila (Figures Eremophila were reported. We were successful in identifying the enzymes responsible for the biosynthesis of these scaffolds and were surprised to discover cis‐prenyl‐diphosphate‐based diterpenoid metabolism in this genus.At the biochemical level, we significantly extended the cognizance of the richness and interesting bioactivities of diterpenoids derived from serrulatane, viscidane and cembrane‐type scaffolds in  Figures , 5, 6. NE. oppositifolia revealed that this species possessed the unique ability to produce monomeric as well as dimeric branched‐chain fatty acids. The occurrence of branched‐chain fatty acids in plants is rare and the presence of dimers of these have not previously been reported in plants (Figure Metabolite profiling of s Figure . The forcis‐prenyltransferases that catalyze the formation of the cisoid‐diterpenoid precursor, nerylneryl diphosphate. Attempts at overcoming this obstacle using yeast/E. coli co‐culturing systems were also unsuccessful because of the inefficient transfer of metabolites between host organisms. These experimental setbacks prevented us from producing any cisoid‐diterpenoids in yeast. Nevertheless, it was indeed a great experience and opportunity to carry out this interdisciplinary research on the unique set of Eremophila samples collected during the 3‐year project period. Throughout the project as well as continuing after the project period we are committed to ensure benefit sharing with the Aboriginal Peoples of Australia. With the extension of our bioprospecting agreement to 2027, we continue to abide by the legal framework outlined herein.A final goal stipulated in our application to the Novo Nordisk Foundation Interdisciplinary Synergy Program was to establish heterologous production systems for some of the natural products isolated that showed interesting bioactivities. We attempted to engineer production systems in yeast but were unable to functionally express the The Plant Journal (Gericke et al., Eremophila was published as a resource article because it provides an account of the huge data set of the natural products discovered and structurally characterized. This means that researchers from other universities and from industries now have access to the data and are free to move ahead using these data also with a mindset of commercialization.Our recent open‐access publication in If you use the information provided here or from our other recent publications to make commercial products, we urge you to strongly consider the Nagoya Protocol requirements to share the benefit with the Aboriginal communities or groups in the areas where these plant species grow. We acknowledge that the work discussed here took place on the lands of Aboriginal Peoples who are the custodians of this land, and acknowledge and pay our respects to their elders, past and present.In the spirit of our bioprospecting agreement and to adhere to our personal wishes of benefit sharing, we include the following statement at the end of this publication:The authors declare that they have no conflicts of interest associated with this work.Appendix S1 Supplementary material.Click here for additional data file.


In humans, aural polyps comprise fibrovascular tissue covered by the respiratory epithelium. Aural polyps with ciliated epithelium are common in cats but are rarely reported in dogs. In a previous case, a mass filled the tympanic cavity alone, and it was surgically removed.To report a case of a canine aural polyp with ciliated epithelium extending from the dorsal tympanic cavity to the external auditory canal with detailed otological features and to demonstrate the usefulness of the transcanal endoscopic procedure (TEP) with a diode laser as a less‐invasive therapy.A 12‐year‐old castrated male Cavalier King Charles Spaniel presented with a 6‐month history of unilateral chronic otorrhoea. Video‐otoscope examination revealed a protruding, reddish and soft‐to‐rubbery round mass in the right horizontal ear canal. Computed tomography and magnetic resonance imaging further revealed a smooth mass extending from the dorsal portion of the tympanic cavity into the horizontal part of the external auditory canal. However, it showed no lesions in the dorsal tympanic cavity.The mass was removed using aural forceps by a traction‐torsion manoeuvre. The suspected base of the mass on the caudal side of the upper tympanic cavity was confirmed by a rigid scope, and it was completely vaporised with a diode laser. Histopathology revealed foci of columnar ciliated epithelium embedded in the connective tissue encapsulated by stratified squamous epithelium. No recurrence was observed at 3 years and 8 months.We describe a rare case of an aural polyp with ciliated epithelium extending from the upper‐middle ear to the external auditory canal in a dog. The TEP using a diode laser may be a useful minimally invasive treatment option for managing external auditory canal polyps. This is the first case report describing an aural polyp with cilliated epithelium extending into the auditory canal in a dog with successful outcome using diode laser. Aural p22.1A 12‐year‐old castrated male Cavalier King Charles Spaniel (CKCS) was referred to Dermatology at the Veterinary Specialists Emergency Centre with a 6‐month history of unilateral chronic otorrhoea in the right ear. This case had been treated with antimicrobials, including minocycline and metronidazole; however, there was no improvement. The dog was clinically healthy and had no neurological signs. A video‐otoscope  examination revealed a protruding, reddish and soft‐to‐rubbery round mass in the right external auditory canal with yellowish purulent ear discharge   revealed a smooth mass extending from the dorsal portion of the tympanic cavity into the horizontal external auditory canal, with a homogeneously enhanced distal portion and heterogeneously enhanced and partially mineralised proximal portion. The horizontal external auditory canal had been focally filled with the mass and fluid  for traction‐torsion via the TEP under general anaesthesia. The external auditory capacity showed no apparent pathologic changes after removing the polyp. The suspected base of the mass around the epitympanic recess on the caudal site of the upper tympanic cavity was confirmed by a rigid scope  and completely vaporised using a diode laser . In this operation, the ear was flushed using a soft feeding tube with neutral electrolysed water. Histopathological evaluation revealed a polypoidal mass with a thick fibrovascular stalk Figure . The les3We report a case of a dog with an aural polyp extending from the upper‐middle ear to the external auditory canal treated with traction and transendoscopic laser ablation. Blutke et al.  reportedThe polyp in the present case had partial central calcification. Similar clinical and histological findings have been reported in human aural polyps Sogebi, . A few fIn the case reported by Blutke et al. , the aur4A dog had an aural polyp with ciliated epithelium extending from the upper‐middle ear to the external auditory canal, which was confirmed by both diagnostic imaging and histopathology. It was successfully removed using transendoscopic traction plus laser ablation of the base without a traditional surgical approach. No recurrence was observed at 3 years and 8 months. TEP using a diode laser seems to be valuable as a less‐invasive approach.No conflicts of interest have been declared.Tomoya Hoshino: conceptualisation; data curation; resources; validation; visualisation; writing – original draft. Shoko Fukuda: validation; visualisation; writing – original draft. Masahiko Nagata: conceptualisation; data curation; resources; supervision; validation; writing – review & editing.The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required as this is a retrospective case report with no original research data.This study has been presented in Asia Meeting of Animal Medicine Specialties in 2019.https://publons.com/publon/10.1002/vms3.845.The peer review history for this article is available at


Perihilar cholangiocarcinoma (PCC) is a complex disorder involving the hepatic hilum. Multiple endoscopic retrograde cholangiopancreatography sessions are necessary for diagnosis and treatment with underlying cholangitis risk. Our aim is to clarify the initial‐drainage‐related prognostic factors of PCC.This study was a single‐center retrospective study. A total of 104 consecutive patients diagnosed with PCC from January 2010 to February 2020 were enrolled. We defined the diagnostic period as the time between the first biliary drainage attempt and the final drainage when treatment, including surgery or chemotherapy, was started. We focused on this initial period and analyzed the endoscopy‐related factors that affected mortality.Overall survival of all PCC patients was 599 days. Overall survival of surgically treated patients and unresectable patients were 893 days and 512 days, respectively. In 48 surgically treated patients, drainage‐related cholangitis within the diagnostic period, defined as new cholangitis that occurred after the first biliary drainage attempt, worsened overall survival from 1460 days to 607 days. Endoscopic sphincterotomy, the first drainage method other than endoscopic nasobiliary drainage, and four or more endoscopic retrograde cholangiopancreatography sessions were risk factors for drainage‐related cholangitis. Drainage‐related cholangitis increased pathological lymph node metastasis. Percutaneous transhepatic biliary drainage as final drainage was the only prognostic factor in unresectable chemotherapy‐treated patients.Drainage‐related cholangitis worsened the prognosis in PCC patients who underwent surgery. Appropriate endoscopic retrograde cholangiopancreatography strategies, especially during the diagnostic period, are of great importance in PCC. Perihilar cholangiocarcinoma (PCC), located at the hepatic hilum, is the most common type of biliary cancer.Biliary obstruction and jaundice are common characteristics associated with PCC. Preoperative biliary drainage of the future remnant liver improves liver function and enhances regenerative capacities of the liver. Incomplete drainage of the remnant liver is a mortality risk when the future remnant liver volume is below 50%.The aim of our study was to clarify the drainage‐related prognostic factors within the diagnostic period from the viewpoints of endoscopists. Biliary drainage and diagnostic ERCP are essential features of PCC diagnosis and treatment. Previous reports concerning PCC have focused mainly on surgical resection and presurgical factors, and few reports have emphasized the importance of factors associated with ERCP. Repeated and inappropriate drainage may trigger cholangitis, which increases postoperative morbidity and interrupts chemotherapy. Identifying the drainage‐related risks associated with PCC will help those performing ERCP determine what should be done and what must be avoided in the primary drainage and diagnosis of suspected PCC.Consecutive patients diagnosed with or treated for PCC at Osaka University Hospital from January 2010 to February 2020 were included. All patients experienced prior expert conferences, and PCC was described as the major prognostic factor. The patients eligible for the study were identified from our hospital databases and were retrospectively reviewed. This study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of Osaka University .Patients with a pathological diagnosis of or presumed PCC according to expert conferences were diagnosed with PCC. We defined the first biliary drainage attempt performed against suspected PCCs as the first drainage. Details of the final drainage are described below. In surgically treated patients, drainage just before hepatectomy, preoperative hospital discharge, or successful neoadjuvant chemotherapy induction represented the final drainage. In unresectable patients receiving chemotherapy, biliary drainage in which chemotherapy could be started and that was associated with hospital discharge was referred to as final biliary drainage. In patients receiving best supportive care, biliary drainage performed just before the best supportive care decision was used as the final drainage. For our investigation of diagnostic ERCP and biliary drainage performed primarily on suspected PCCs, we defined the period between the date of the first drainage and final drainage as the diagnostic period Figure . EndoscoCholangitis was diagnosed according to the Tokyo Guidelines 2018.Successful biliary drainage was defined as a decrease in the total bilirubin level by 50% or reaching the normal limit within 14 days.Overall survival (OS) was the time from the first visit to the hospital with assumed PCC to the date of death regardless of the cause or the last date of the hospital visit. Time to diagnosis was the time from the first visit to the hospital with suspected PCC to the date of the first pathological diagnosis. For staging, the criteria of the 6th version of the general rules for clinical and pathological studies on cancer of the bile duct published by the Japanese Society of Hepatobiliary‐Pancreatic Surgery were used. Staging and Bismuth classification were identified clinically with contrast‐enhanced multidetector computed tomography/magnetic resonance imaging before drainage or ERCP. Clinical lymph node metastasis was defined as fluorine‐18 deoxyglucose accumulation with positron emission tomography‐computed tomography (CT) or a minor diameter over 10 mm based on CT.The primary endpoint of this study was to clarify the drainage‐related prognostic factors within the diagnostic period. We focused mainly on the factors related to diagnosis and biliary drainage from the viewpoints of endoscopists. The variables associated with patient characteristics and ERCP procedures were retrospectively collected based on medical records.p‐value below 0.05 was considered significant. All statistical analyses were performed with JMP Pro 15 .The data are shown as median values with the range or IQR unless otherwise specified. For the univariate analysis, the Mann‐Whitney U test was used for continuous variables, the Wilcoxon rank‐sum test was used for ordinal scale variables, and the chi‐square test was used for categorical variables. A Cox proportional hazard model was used for univariate and multivariate analyses of prognostic factors. A logistic regression model was used for multivariate analysis to analyze the risk of related factors. For the multivariate analysis, factors shown to be significant in the univariate analysis were applied. OS was estimated with the Kaplan–Meier method and statistically evaluated by the log‐rank test. A A total of 119 patients were presumed to have PCC from January 2010 to February 2020 at Osaka University Hospital Figure . FifteenThe median survival time (MST) of the 104 PCC patients was 599 days Figure . Univarip = 0.003, Table p = 0.0005, Figure p = 0.042), ENBD as first drainage , and four or more ERCP/PTBD sessions within the diagnostic period  were independent factors of drainage‐related cholangitis  and chemotherapy treatment time of 56 unresectable patients and 44 patients who underwent chemotherapy were analyzed by the Kaplan‐Meier method. a) The median survival time (MST) of unresectable patients was 512 days. b) Unresectable patients who received chemotherapy had a longer OS than those who did not receive chemotherapy . c) Unresectable patients with Percutaneous Transhepatic Biliary Drainage (PTBD) had a shorter OS than those without PTBD . d) Chemotherapy patients with PTBD had a shorter OS than those without PTBD .Click here for additional data file.Table S1. Prognostic factors for unresectable perihilar cholangiocarcinoma patientsClick here for additional data file.Table S2. Prognostic factors for unresectable chemotherapy‐treated patientsClick here for additional data file.


Photovoltaic silicon converts sunlight in 95% of the operational commercial solar cells and has the potential to become a leading material in harvesting energy from renewable sources, but silicon can hardly convert clean energy due to technologies required for its reduction from sand and further purification. The implementation of the novel materials into photovoltaic systems depends on their conversion efficiency limited by the material's inherent properties, longevity dependent on internal stability, and ease of manufacturing process. A major challenge is discovering a multilayered set of different photovoltaic materials capable of converting clean energy from a wider spectra range since emerging materials and technologies such as dye‐sensitized and quantum dots suffer from low conversion efficiencies while perovskite and organic cells have short longevity in atmospheric conditions. Presently, improving technologies for commercialized materials and creating multijunction solar cells enhanced by new photovoltaic materials is a path toward cleaner energies. With the rapid development of the integrative technologies and challenges that photovoltaics for clean energy conversion are facing, the entire clean photovoltaic industry could arise by bottom‐up course as a part of integrative technologies rather than erecting large power plants. Major determinators in distinguishing photovoltaic materials are conversion efficiency, energy payback, and cost‐per‐kilowatt. Nowadays, silicon is a leading material for renewable conversion of sunlight into electricity. The future clean photovoltaic conversion based on emerging materials may rise by bottom‐up principle as part of integrative technologies rather than the addition to the existing grid network or erecting large power plants. The global oil crisis in 1974 pushed research toward photovoltaic materials different from silicon resulting in the commercialization of the second‐generation thin‐film solar cells. Increased awareness regarding the sustainability of our habitat and extensive use of fossil fuels at the beginning of the 21st century resulted in large governmental subsidies toward renewable energy sources. Consequently, the photovoltaic industry base shifted from small privately owned vendors to large companies with industrial size production and installation capacities. Simultaneously, the research regarding the photovoltaic phenomenon has moved from a few leading labs to virtually every lab around the world. In the early 2020s, we are in the middle of the pandemic, followed by damaged communication and supply lines, and at the beginning of the incoming energy crisis. These circumstances will inevitably lead to a higher share in energy consumption from already commercialized first and second‐generation solar cells, push further development of the new photovoltaic materials and technologies, and faster commercialization of the third‐generation solar cells.Major socioeconomic shifts on the global scale inevitably induce harsh periods for human societies, but these periods were traditional triggers for advancements in the photovoltaic sector Figure1. Duri which makes ideal conditions for solar cells: clear skies with low air temperatures that further increase the efficiency of solar cells.Figure2 standard size while the above‐mentioned Canadian regions would need two‐thirds of that area. In 2021, premium commercially available systems provide guaranteed 350 W power with 30 years warranty that further reduces the required size of photovoltaic surface and longevity of installed photovoltaic systems.The key advantage of photovoltaic technologies that makes them the most promising area of all renewable energy sources is that it does not pollute the environment in which operate, has no moving parts while having a lifespan of several decades with a low level of maintenance and monitoring. The photovoltaic technology does not require extremely high installation costs and it could be independent of the existing electrical network. Photovoltaic systems are easily installed in homes, public or commercial buildings, where their use is safe and silent. Remote and underdeveloped areas can easily produce their electricity by starting with a small energy system and further planning a gradual increase in capacity along with the increase in energy needs. Extremely low initial costs compared to erecting a traditional electricity grid make solar energy utilization the most preferred option in developing countries, where photovoltaic energy conversion is the fastest growing segment of the energy sector. Simultaneously, in some developed countries such as Canada, modular and decentralized photovoltaic technology is more effective than investing in long power transmission lines and is thus ideal for meeting the electricity needs of many remote households where the supply of electricity from the grid is unprofitable. For example, the most of Canadian Prairies lands are also one of the sunniest areas on the planet with 2350 h of direct sunlight a year,10 whiThe rapid development of new photovoltaic materials and technologies, and discoveries of the new material properties and conversion mechanisms require a constant update on inflowing data, where some widely accepted definitions and terminology are changing. The most commonly used classification of solar cells in the present time originated from the early commercial vendors of photovoltaic systems. Arranging photovoltaic materials into the first, second, and third generation solar systems refers to the sequence of introducing a particular technology to the global market. While the first and second generations of solar cells are matured regarding worldwide commercial distribution networks and are well investigated by researchers, most new photovoltaic materials and technologies introduced in the last two decades are classified into the third generation regardless of photovoltaic material, manufacturing technology, or conversion mechanism. Given many newly developed materials sensitive to incident light coming from the sun, this report emphasizes the need for narrowing and reiterating criteria and classification parameters regarding photovoltaic phenomena and related photovoltaic materials and technologies. Together with emphasizing the crucial parameters in distinguishing photovoltaic materials from a larger family of photosensitive materials Sections  and 4, t2 Electricity generated by solar systems accounted for 3.1% of global electricity generation positioning photovoltaics as the third‐largest renewable electricity technology behind hydropower and wind. Since silicon solar cells are present in the market for half of the century, ≈95% of the operational commercial solar cells in 2020 where based on silicon where the share of the higher quality mono‐crystalline technology raised to 84%, compared to 66% in 2019. The major producer of high purity silicon for the electronic industry remains to be Wacker Chemie aktiengesellschaft (Germany/USA), the same company that developed the Siemens process in the 1950s. Regarding the production of lower grade 6N solar poly silicon, China is a world leader by far in both annually installed capacity and overall production of the photovoltaic systems. According to the International Renewable Energy Agency, China's installed solar cell system capacity was around 254 GW in 2020, about 50 GW higher than in 2019. These values will continue exponential growth as depicted in Figure the construction of the 400 GW solar and wind plants in desert areas started in 2021 with an expected commission in 2025 and further lead toward China's promised carbon neutral target by 2060. Further in the future, such developments may reach a plateau percent‐wise due to grown installed capacity but capacity wise these numbers will be noticeably higher each year.In a few decades, photovoltaics‐based energy conversion technologies have evolved into a self‐sustained industry that experiences the highest growth in the renewable and green sector. Power generation from photovoltaic systems in 2020 is increased by 156 TWh that is 23% higher than in the preceding year.12 Ele Increased power for the equal amount of photovoltaic material further leads to a lower cost per kW value for new photovoltaic systems not only due to less used photovoltaic material but also other equipment  used to convert energy inside photovoltaic material and to deliver this electricity to the grid.The power output of the commercial multisilicon solar cells rose significantly from below 250 W 10 years ago to over 350 W nowadays. Development of the new photovoltaic materials is hindered in statistics‐based reports because about 95% of the commercial solar cells are based on silicon due to its long‐term presence in the market. However, the reports on emerging photovoltaic materials and technologies are stating the great increase in conversion efficiencies in the third‐generation solar cells. Regardless of the photovoltaic material or manufacturing technology, current innovations lead to increased solar systems’ overall capacity and power output without significantly increasing the manufacturing costs.21 Inc3 Photovoltaic materials are traditionally defined by their unique ability to convert solar radiation into electricity. However, with the entering of, for example, quantum dot solar cells, photosynthesis emulative processes, or photocatalytic green hydrogen production where energy is used for chemical reactions, the traditional definition of photovoltaic materials is becoming doubtful. Some materials can exhibit sensitivity to solar radiation but cannot sustainably generate electricity. For example, a vast number of inorganic compounds are photosensitive but hardly all of them can be used as sustainable photovoltaic material. Nevertheless, as some material converts sunlight to electricity, the value of generated power should exceed the amount of energy invested in extracting or synthesizing the photovoltaic material, and degradation of the conversion efficiency throughout service time should be prolonged enough to satisfy efficacy standards. Phenomena such as upconversion can be used for sensors while downconversion is commercialized in light emitting diode lighting, but both processes require more energy that can bring back to the electrical circuit. Table2 payback time will become another unavoidable determinator in photovoltaic materials considerations.With the ever‐growing number of new materials and compounds where many show sensitivity to incident sunlight, the distinction between photosensitive and photovoltaic materials becoming unclear, in particular in the early stages of research.23 PhoFigureWith each innovation in design and technology, newer types of photovoltaic materials improve characteristics and more controllable synthesis procedures. Regardless of the material, technology, or conversion mechanism, each photovoltaic cell has to satisfy key properties that characterize solar cell systems Figure4. The 4The eventual implementation of the novel material into commercialized photovoltaic systems mainly depends on their conversion efficiency limited by the inherited properties of the photovoltaic component defined by Shockley–Queisser limit, longevity dependent on internal stability, and ease of the manufacturing process. The materials with photovoltaic characteristics are often classified based on the period when particular material and technology become commercial. The current market is almost exclusively covered by the first and second solar cell generations. First‐generation silicon and gallium‐arsenide solar cell systems characterize moderate conversion efficiencies but excellent structural and internal stability and well‐known production technologies. The thin‐film technologies are often referred to as the second‐generation solar cells that have lower conversion efficiencies compensated by low manufacturing cost and ease of installation on various surfaces. The recently developed technologies and novel photovoltaic materials are coming in a great variability of designs, materials, and manufacturing methods that have great potential regarding theoretical conversion efficiencies, low manufacturing costs, scalability, flexibility, etc. However, a common challenging factor for all novel photovoltaic systems is its steadiness and strength over a long time, leading to the conclusion that the leading role of silicon as a major commercial photovoltaic material will finish once new material and technology achieve at least internal stability and longevity of the silicon solar cells systems.4.1 Far beyond multijunction solar cells, perovskite/Si tandem solar cells reached 29.5% conversion efficiency while other emerging photovoltaic materials, e.g., organic or quantum dots cells, have conversion efficiencies below 20%. Among silicon and thin‐film solar cells, heterostructures silicon and copper indium gallium selenide (CIGS) have the highest conversion efficiencies at 27.6% and 23.4%, respectively. FigureThe solar spectrum has a wide range, from 100 to 10 000 nm where the visible part of the spectrum is between 400 and 700 nm. Considering the large spectra of the solar spectrum, numerous materials absorb this energy and produce different phenomena rather than the photovoltaic effect. The different photosensitive materials convert electromagnetic energy only in a specific spectral range. Hence, a rather large part of the incident sunbeam would not excite electrons because some photons do not have enough energy, e.g., photons below 1.1 eV in silicon‐based solar cells while photons with surplus energy transform their surplus into heat that reduces the overall efficiency of the solar cells. Each photovoltaic material has a unique theoretical maximum limit of conversion efficiency, i.e., nearly 29% for mono‐crystalline silicon. Besides inherited losses regarding bandgap value for particular photovoltaic material, there are various losses related to the entire system responsible for converting the sun's energy to electricity, e.g., optical losses, reflections of incoming rays, electrical resistance losses, material contamination, surface and crystal defects, etc. Researchers from the National Renewable Energy Laboratory (NREL) demonstrated the world's highest 47.1% conversion efficiency solar cell operated under the direct spectrum at 143 Suns concentration, using a monolithic‐series‐connected six‐junction inverted metamorphic structure.28 Far4.2 In first‐generation solar cells, the structural and internal stability of silicon solar cells were rarely discussed. Some solar cells of the first generation are still operational, 40 years after its installments. One of the major drawbacks of third‐generation solar cells is their internal stability over a long time. While some scientists claim that there are no insurmountable barriers regarding the internal stability of the solar cells, each material with photovoltaic capabilities does have its unique inherited limitations that are difficult to mitigate. For example, in the first two decades of the 21st century, a technological breakthrough is made in synthesizing organic or hybrid photovoltaic research but despite their low production cost and low environmental impact, their market share remains small due to the vulnerability of the organic components on atmospheric or bio microbial impacts. Some concept solar cells like black silicon imply structural stability similar to the first generation solar cells why some quantum dots materials preserve internal stability by being encapsulated inside a transparent body. However, uncertainties regarding molecular stability on temperature increase in organic and some hybrid solar cells, as well as the toxicity of some components, are yet to be answered on the research level before entering the development and eventually commercialization phase.The conversion efficiency data alone does not give information on how long solar cells provide maximum output and how long these solar cells can keep photovoltaic properties after its syntheses.33 In  solar cells manufactured after 2000 have degradations rates 0.4%, 0.6%, 1.0%, and 0.5%, for mono‐Si, poly‐Si, a‐Si, and CdTe solar cells, respectively. Currently, First Solar from California claims the lowest degradation rate in the market. Series 6 CuRe has a 0.2% degradation rate during a 30‐year warranty achieved by replacing copper with elements from the fifth column of the periodic table . An indicative observation is that degradation in first and second solar cell systems is below one percent per year and is mainly attributed to the solar cell parts rather than to the photovoltaic material itself. In opposite, third‐generation solar cells suffer from two digits degradation rates mostly attributed to the internal stability of the photovoltaic materials. Photovoltaics based on organic materials, even on a laboratory scale, are hardly achieving efficiencies above 10% while organic compounds easily decompose under incident light often reducing the lifespan of panels to months or weeks instead of years.The degradation rate of the silicon and thin‐film solar cells is widely available in literature since their commercial use started five decades ago. Most photovoltaic‐module manufacturers offer a 25‐year or 30‐year warranty that corresponds to a power drop of less than 20% within the warranty period or ≈0.6–0.7% a year. According to an NREL report35 sol4.3 Nowadays, major suppliers of silicon solar panels guarantee efficiencies above 24% with 30 years of warranties that are very close to the best laboratory results. Second the best commercial solar cell LG NeonR N‐Type solar modules have guaranteed efficiency of 22% at 380 W maximum power that is double the capacity of what was available in the early 2010s. Such rapid advances in solar cell efficiencies were not forecasted even by the most respected experts and government agencies, e.g., Japanese PV2030 road map from 2006 setting required efficiencies of 22% should be reached by the year 2030 for module and the wafer thickness to 50–100 µm. However, these advances were not achieved by discoveries and implementations of the new technologies but rather by small step improvements in every step in the rather long process of producing silicon solar cells from sand.Advancements in manufacturing processes led to the specifications of the commercial solar systems being close to calculated Shockley–Queisser limits of the particular photovoltaic material.38 NowFigureThe vast majority of currently made commercial solar cells are designed to convert solar energy by using silicon as the main photovoltaic material. Almost the entire commercial production of feedstock silicon with required photovoltaic characteristics is based on the same process steps with very little processing or technological variations Figure6. Meta5 estimated the life‐cycle energy requirement for crystalline silicon between 2700 and 5200 MJ m−2 and greenhouse emission rate from 23 to 45 g CO2‐eq kWh−1. Further refining up to solar grade quality requires even more corrosive gases such as halogenic silanes. Regardless, those productions of solar panels become highly automated processes contributing to a decrease in cost per kW value but automated processes are also consuming energy. Aluminum frames, ethylene vinyl acetate, wires, and glass sheet are important components of solar panels that require energy for their production. Apart from manufacturing the components, energy is expended for obtaining raw materials, processing, testing, packing, transportation, and installation of solar panels, where each step has an impact on the environment. The photovoltaic industry developed relatively recently and recycling solar panels at the end of their service time will become another environmentally challenging task. Revealed by recent global geo surveillance, the global inventory of commercial, industrial, and utility‐scale photovoltaic (PV) installations overlay the most valuable arid lands, which requires changes in policymaking toward installations in remote areas unaffected by human and biodiversity activities.Historically, new technologies were acquired and developed based on profitability estimates. Nowadays, societies with established environmental concerns related to environmental impact, sustainability, reusability, or recyclability would prevail toward environmentally friendlier technologies instead of pure profitability assessment. Photovoltaic systems are produced from a variety of technologies that have an impact on the environment. The most commonly used photovoltaic material silicon is produced from quartz by a carbothermic process that consumes a lot of energy and emits a significant amount of carbon dioxide from sources like coal or carbonaceous fossil fuel. Sice et al.41 est2‐equivalent are becoming major determinator in photovoltaic considerations. In perspective, CO2‐eq kWh−1 will replace cost‐per‐watt parameter as key human motivator , copper–indium diselenide, or organic photovoltaic materials. This may happen, but so far, based on reliability, performance, and lifetime, none of these alternatives appear to be in a position to challenge silicon solar cells.46 Occ Along with environmental sustainability, the key advantage of the emerging photovoltaic materials should be its scalability. First generation GaAs PV cells would require 40 years of today's gallium production capacity to reach one terawatt (TW) electricity generation while second generation thin‐film CdTe modules would require 80 years of today's tellurium, and thin‐film CIGS would require 32 years to achieve the same goal. Likewise, it would only take a few days to scale up perovskites’ production capacity to the one TW level while some emerging photovoltaic materials would require even less time. The only commercial photovoltaic material that is scalable to this level is silicon, which for one TW electricity generation capacity would require around 80 d of our current silicon production.If the photovoltaic industry aiming to become the primary source of energy, that means the size of today's photovoltaic systems requires a tremendous capacity increase in a brief time.47 Alo7 where increasing renewable energy share to 38.5% is essential to achieve the agreed objectives. Increasing the market share of new photovoltaic materials inevitably leads to further improvement in the photovoltaic field. Considering increased awareness regarding our natural habitat and global consensus regarding replacing fossil fuels with renewable sources of energy, further advancement will continue. Most strategic plans rely on incorporation of the renewable sources of the energy into the existing high power density systems. Inherited lack of long‐term stability and rapid degradation in atmospheric conditions are unsolvable drawbacks for emerging photovoltaic materials in competition with not only fossil fuels but with first and second generation of the photovoltaic materials. However, emerging photovoltaic materials become preferable materials in net‐zero energy buildings, transportation vehicles, agri‐lands, specialized habitats or entire human habitation systems. The environmental and economic evaluation of the household energy management connected to high power density systems and the solar system always gives the same outcome; grid connected is significantly lower‐cost while solar systems are solutions are less impactful on environment. Integrating emerging photovoltaic materials into urban environment where buildings infrastructure provides better protection from atmospheric influences and better cooling may mitigate some of its key hindrances of the emerging photovoltaic materials.The European Union in its European Green Deal set the goal of reducing 55% of its greenhouse gas emissions by 2030 and becoming the completely climate neutral by 205051 whe recently stated that flexible perovskite/c‐Si tandem technology with excellent 27.6% conversion efficiency is the most competitive candidate for the next generation mass‐produced solar cells integrated on the buildings’ exterior while Roger et al. suggested technological solutions for commercially viable production of similar material. Simultaneously, flexible photovoltaic materials capable of high‐power conversion efficiency in the low light environments become developed for indoor applications while near‐infrared dye‐sensitized solar cells can satisfy high aesthetic requirements, if required. Researchers from the German Aerospace Center gave a substantial report regarding adopting solar cells into versatile applications, including buildings, vehicles, extraterrestrial applications, etc.Considering cleaner methods for energy conversion, photovoltaics become a key component of the relatively new scientific discipline: integrative technologies. Wu et al.54 rec2 equivalent emission become available.In a view of the integrative technologies, it may happen that the entire clean photovoltaic industry may naturally rise by bottom‐up principle as part of integrative technologies rather than the traditional top‐down approach by extensively planning, financing and finally erecting large power plants on valuable landfills. In the next decade, we will witness total energy consumption significantly deviates from the consumption from the grid networks that would indicate a significant intake of the emerging photovoltaic technologies integrated with buildings, agricultural fields, vehicles, road infrastructure, etc. Further integration of photovoltaic materials into human habitats will continuously decrease an environmental impact of these materials until finally new net‐zero energy technologies with zero values for CO8 A variety of the materials and technologies implemented in third‐generation solar cells indicate even higher conversion efficiencies in a laboratory environment, but the internal stability of the photovoltaic materials limits their implementation on an industrial scale. Major determinators in distinguishing photovoltaic materials from the larger family of photosensitive materials are conversion efficiency, energy payback, and cost‐per‐kilowatt. Further assessment regarding the commercialization of the photovoltaic materials relies on the internal stability of the photovoltaic material, manufacturing technology, and environmental impact of the process. In the meantime, before photovoltaic materials for sustainable clean energy are found, paradoxically, photovoltaic silicon that is produced by environmentally intensive processes will remain the leading material for converting sunlight into electricity. With the rapid development of the integrative technologies and challenges that photovoltaics for clean energy conversion are facing, it would not be a surprise if the entire clean photovoltaic industry arises as a part of integrative technologies rather than building large power plants as part of the existing network.In a shift toward clean energies, photovoltaic technologies are the most promising solution to the global ever‐growing energy demand. A significant number of new photovoltaic materials will find their market. Commercialized in the previous century, photovoltaic materials used in the first and second‐generation solar cells reached their inherited conversion efficiency limits and their further improvements rely on advancements in photovoltaic systems rather than on the material itself. If only conversion efficiency is considered, some third‐generation multijunction cells introduced in the market achieved energy conversion rates above 40%.59 A vThe authors declare no conflict of interest.


An 11‐year‐old girl with cervical node ALK+ anaplastic large cell lymphoma (ALCL) in remission for 3 years after chemotherapy complained of dull ache in the lower part of both legs just above the heels. About 2–3 months later she sustained an accidental blunt injury to the lower part of the right (R) leg for which her parents sought medical attention. On examination, there was a fluctuant but tense swelling in the posterior aspect of the R lower leg (Figure We would like to highlight this unusual site of extranodal relapse of ALCL, occurring in the soft tissue surrounding the Achilles tendon and masquerading as a posttraumatic hematoma.The authors declare no conflict of interest.


Understanding how biodiversity is changing over space and time is crucial for well‐informed decisions that help retain Earth's biological heritage over the long term. Tracking changes in biodiversity through ecosystem accounting provides this important information in a systematic way and readily enables linking to other relevant environmental and economic data to provide an integrated perspective. We derived biodiversity accounts for the Murray–Darling Basin, Australia's largest catchment. We assessed biodiversity change from 2010 to 2015 for all vascular plants, all waterbirds, and 10 focal species. We applied a scalable habitat‐based assessment approach that combined expected patterns in the distribution of biodiversity from spatial biodiversity models with a time series of spatially complete data on habitat condition derived from remote sensing. Changes in biodiversity from 2010 to 2015 varied across regions and biodiversity features. For the entire Murray–Darling Basin, the expected persistence of vascular plants increased slightly from 2010 to 2015 (from 86.8% to 87.1%), mean species richness of waterbirds decreased slightly (from 12.5 to 12.3 species), whereas for the focal species the estimated area of habitat increased for 8 species and decreased for 1 species. Regions in the north of the Murray–Darling Basin generally had decreases in biodiversity from 2010 to 2015, whereas in the south biodiversity was stable or increased. Our results demonstrate the benefits of habitat‐based biodiversity assessments in providing fully scalable biodiversity accounts across different biodiversity features, consistent with the United Nations System of Environmental Economic Accounting – Ecosystem Accounting (SEEA EA) framework. Understanding how biodiversity is changing over space and time is crucial to making well‐informed decisions that help retain Earth's biological heritage. Given the escalating species extinction crisis IPBES, , reliablIn responding to these needs, a range of biodiversity monitoring and reporting initiatives have been implemented around the world. These initiatives notably include reporting under the Convention on Biological Diversity (CBD), such as the Global Biodiversity Outlook  framework to standardize the quantification of stocks of ecosystem assets, including biodiversity and flows of ecosystem services over time UNCEEA, . The SEEIn the SEEA EA, biodiversity is considered under a “thematic account” that is additional to the core ecosystem accounts UNCEEA, . The SEETo populate biodiversity accounts under the SEEA EA, the most rigorous data source is field observations of species occurrences, population abundances, and community diversity, such as those acquired through ecological monitoring surveys. While these observations provide direct indications of the status of species and communities , including significant irrigated agriculture from diverted water flows  in the ecosystem accounting area, given changes in habitat condition, was determined using the approach described by Ferrier et al.  spatial resolution across the New South Wales and Australian Capital Territory Regional Climate Model (NARCLiM) region of southeastern Australia , painted honeyeater (Grantiella picta), superb parrot (Polytelis swainsonii), growling grass frog (Litoria raniformis), koala (Phascolarctos cinereus), rigid spider‐orchid , winged pepper‐cress (Lepidium monoplocoides), river swamp wallaby‐grass (Amphibromus fluitans), river red gum , and black box .A habitat‐based approach was also used in accounting for a number of species. The approach combined remote sensing of land‐cover attributes with best‐available mapping of the original spatial distribution of each focal species  spatial distribution for each focal species  from 2010 to 2015 Table .Importantly, these species‐level assessments were intended to identify habitat areas within the potential extent of occurrence of each species. They did not predict where each species actually occurs. Errors in land‐cover classification, or in translating land‐cover categories to habitat, may result in under‐ or overestimation of habitat area within the potential extent of occurrence.Our assessment indicated that the regions in the north of the Murray–Darling Basin generally had more negative changes in biodiversity from 2010 to 2015, whereas the southern regions tended to have more positive changes Figure . No regiThe regions with the largest relative increase in biodiversity were the Campaspe and Goulburn‐Broken for plant species persistence (+0.6%) Appendix , the LacOur habitat‐based approaches to accounting for biodiversity in the Murray–Darling Basin provided highly resolved information on changes in biodiversity expected to have occurred across the region as a function of observed changes in habitat condition, aligned with the SEEA EA framework UNCEEA, . HoweverAdvances in habitat condition modeling and prediction will be of substantial benefit, including development of new fine‐resolution annual spatial layers. This will enable consideration and quantification of more immediate changes in habitat and biodiversity within a yearly accounting period, rather than relying on data over a longer preceding period as applied here . Such advances require novel solutions to account for the effects of natural interannual climate variability on vegetation as quantified by space‐borne sensors  would enable a more direct quantification of the relative status for accounts. Essentially, this would involve a counterfactual scenario of expected waterbird diversity in a pre‐intensification reference state (McNellie et al., For the focal species accounts, more finely resolved spatial data on the potential extent of occurrence would also provide an improved baseline and enable reporting of habitat area relative to pre‐intensification reference state. The spatial data we used for potential extent of occurrence DAWE,  were of Accounting for biodiversity has significant potential in helping track biodiversity change in a consistent way over space and time. Incorporating these accounts with broader SEEA EA ecosystem accounts offers the opportunity for better understanding the drivers and consequences of biodiversity change, including environmental, social, and economic factors (UNEP‐WCMC, Additional supporting information may be found in the online version of the article at the publisher's website.Click here for additional data file.


Osteoclasts are large multinucleated cells from hematopoietic origin and are responsible for bone resorption. A balance between osteoclastic bone resorption and osteoblastic bone formation is critical to maintain bone homeostasis. The alveolar bone, also called the alveolar process, is the part of the jawbone that holds the teeth and supports oral functions. It differs from other skeletal bones in several aspects: its embryonic cellular origin, the form of ossification, and the presence of teeth and periodontal tissues; hence, understanding the unique characteristic of the alveolar bone remodeling is important to maintain oral homeostasis. Excessive osteoclastic bone resorption is one of the prominent features of bone diseases in the jaw such as periodontitis. Therefore, inhibiting osteoclast formation and bone resorptive process has been the target of therapeutic intervention. Understanding the mechanisms of osteoclastic bone resorption is critical for the effective treatment of bone diseases in the jaw. In this review, we discuss basic principles of alveolar bone remodeling with a specific focus on the osteoclastic bone resorptive process and its unique functions in the alveolar bone. Lastly, we provide perspectives on osteoclast‐targeted therapies and regenerative approaches associated with bone diseases in the jaw. The jawbone is morphologically and functionally different from other skeletal bones. It is originated from migrating cranial neural crest cells and forms through primarily intramembranous ossification which differs from the axial and appendicular skeletons that arise from the mesoderm and undergo endochondral ossification. The alveolar bone is the part of the jawbone that displays anatomically and functionally unique characteristics. It retains the teeth through periodontal fibers called periodontal ligament (PDL) and is constantly subjected to strains with occlusal forces during mastication. Since this complex structure develops during tooth eruption, it does not regenerate easily once the tooth is lost. Therefore, it is crucial to understand the unique tissue structure and biological function of the alveolar bone for treating diseases and regenerating lost tissues.Bone remodeling is a process whereby bone is constantly removed and replaced with new bone. These two distinct events, resorption and formation, are well coordinated in a temporal and spatial manner to maintain skeletal integrity; their dysregulation is associated with bone diseases in the jaw. Osteoclasts are multinucleated cells derived from the hematopoietic lineage and have the ability to resorb bone matrix. Osteoclastic bone resorption is controlled by several mediators such as RANKL and OPG. Inhibiting the mediators of osteoclast differentiation and activity to resorb bone can result in an increase in bone mass. For this reason, it is important to understand the mechanisms of osteoclastic bone resorption specifically associated with bone diseases in the jaw. This review will address the mechanism of alveolar bone remodeling with a specific focus on recent advances in understanding the mechanisms of osteoclast differentiation and function. Lastly, we provide perspectives on osteoclast‐targeted therapies and regenerative approaches associated with bone diseases in the jaw.2Bones are derived from three distinct embryonic origins: the paraxial mesoderm, lateral plate mesoderm, and neural crest. The somites developed from the paraxial mesoderm generate the axial skeleton and the cephalic mesoderm, a part of the paraxial mesoderm, generates the posterior cranial bones, the lateral plate mesoderm generates the limb skeleton, and the cranial neural crest generates the anterior craniofacial bones  in the jaw forms through intramembranous ossification and originates from the cranial neural crest‐derived dental mesenchyme consisting of the dental follicle which surrounds the developing tooth germ Figure . During The alveolar bone is a complex structure that rests on the basal bone of the maxilla and mandible and forms the tooth sockets Hassell, . It is a3Osteoclasts are large multinucleated cells that originated from hematopoietic stem cells (HSCs) and are responsible for bone resorption Figure . The HSCRankl in mice leads to severe osteopetrosis  and receptor activator of nuclear factor‐κB ligand  located in the ruffled border membrane transport protons to acidify the resorption compartment  in the alveolar bone of the maxilla (19.1%/year) and mandibular (36.9%/year) is 3‐ to 6‐fold higher than the femur (6.4%/year) in dogs  or anabolic  , Tannerella forsythensis (T. forsythensis), and Treponema denticola (T. denticola), known as the “red complexes” in a severity‐ranked hierarchy of disease‐causing bacteria, are considered as periodontal pathogens  in which proline‐to‐arginine (P416R) missense mutation is introduced in the mouse Sh3bp2 gene, hyperactive macrophages produce high amounts of TNF‐α that drive systemic inflammation and stimulate secretion of RANKL and M‐CSF from stromal cells, leading to excessive osteoclastic bone resorption (Ueki et al., Cherubism is a rare autosomal dominant disorder caused by mutations in the SH3BP2 gene (Ueki et al., 5.4Rankl in osteocytes leads to reductions of osteoclast cumbers and orthodontic tooth movement (Shoji‐Matsunaga et al., Rankl gene to the periodontal tissue promotes osteoclastic bone resorption and accelerates tooth movement in rats (Kanzaki et al., Opg gene inhibits RANKL‐mediated osteoclastic bone resorption and prevents tooth movement (Shoji‐Matsunaga et al., Orthodontic tooth movement is a well‐coordinated biological process that induces alveolar bone remodeling by selectively applying sustained forces to teeth. During orthodontic tooth movement, bone resorption by osteoclasts occurs at the compression side of the tooth socket, compressing PDL fibers, and osteogenesis by osteoblasts occurs at the tension side of alveolar bone (Vavidovitch, 5.5Osseointegration is defined as a direct structural and functional connection between bone and the surface of a dental implant, used to replace lost dentition (Branemark et al., Mechanical stress on the dental implant provides positive or negative consequences for bone tissue. Under normal functional load, osseointegration is enhanced around the dental implant (Berglundh, Abrahamsson, & Lindhe, As anti‐resorptive agents are effective for treating osteolytic conditions including Paget's disease and osteoporosis, bisphosphonate‐coating to the implant surface improves the early fixation of implants (Abtahi, Tengvall, & Aspenberg, To achieve successful use of dental implants in clinical setting, the balanced activities of osteoclasts and osteoblasts are essential. Therefore, understanding the mechanism of osteoclast interactions with dental implants provides new insights to design suitable implant surfaces and materials for alveolar bone regeneration. Furthermore, recent technological advances in tissue engineering approaches offer a new type of dental implants called “bio‐hybrid implants” that provide PDL and cementum attachment on the surface of implants and restore the physiological function of the tooth and periodontium (Lee et al., 6Bone resorption by osteoclasts is an essential process to initiate bone remodeling and maintain bone homeostasis. Recent technological advances in live imaging and lineage‐tracing studies in bone have provided new insights into osteoclast biology and opportunities for therapeutics targeting osteoclast functions to treat bone diseases. The alveolar bone exhibits anatomically and functionally unique characteristics compared to axial and appendicular skeletons. Therefore, it is crucial to evaluate the function of osteoclasts in alveolar bone remodeling with advances in technology, which ultimately contributes to understanding the mechanisms underlying jawbone‐specific diseases and overcoming the limitations of current therapies and bone regeneration applications. More comprehensive analyses of the cellular and molecular mechanisms of alveolar bone remodeling will certainly provide more options in clinical dentistry.All authors declare no conflicts of interest.


Non‐secretory multiple myeloma (NSMM) is an extremely rare variant of multiple myeloma (MM) and accounts for a maximum of 5% of all myeloma cases. This variant of MM usually represents a diagnostic challenge to the clinician because of the absence of detectable monoclonal immunoglobulin on serum or urine electrophoresis. We present the case of a 34‐year‐old Caucasian male who presented to the emergency department with pain in the lumbar area secondary to a fall and who was eventually diagnosed with non‐secretory multiple myeloma after the radiologist initially pointed out a discrete “salt and pepper” infiltration of the spine seen on magnetic resonance imaging (MRI) although the spine computed tomography (CT) performed initially showed no suspicious lesions for malignancy. The final diagnosis was obtained after a positive bone marrow biopsy together with the presence of malignant lesions seen on the spine MRI. This case points out the importance of different bone marrow involvement patterns seen on MRI and other useful sequences the radiologist could use to better discriminate between normal marrow reconversion and malignant infiltration. We describe this case report to raise awareness among medical practitioners and radiologists of the extreme importance of subtle bone marrow infiltration patterns seen on MRI, which could help diagnose multiple myeloma at an early stage. Non‐secretory multiple myeloma (NSMM) on the contrary is a rare variant of MM which accounts for a maximum of 5% of all myeloma cases and is even much rarer in young people.Both entities have the same clinical and imaging features. However, in the case of NSSM, the plasma cells fail to secrete an immunoglobulin, and therefore, both the serum and urine electrophoresis are normal.The use of MRI in the diagnosis and staging of MM has increased within the last decades, MRI being more sensitive than computed tomography and X‐rays in the detection of focal MM lesions, as well as subtle medullary infiltration.We present the case of a patient with non‐secretory multiple myeloma that was diagnosed at an early stage, before end‐organ damage, thanks to the extreme sensitivity of MRI in depicting marrow infiltration, changes that in numerous instances are visible before any clinical or serological abnormalities are observed.2A 34‐year‐old male patient presented to the Emergency Department of the Regional Hospital, complaining of lumbar back pain after a fall from a 2‐m height. The lumbar spine CT was normal Figure , demonstAfter extensive laboratory results, nothing but discrete anemia was noted; there was no detectable monoclonal immunoglobulin on serum or urine electrophoresis Table .The patient continued to complain of worsening lumbar pain for the next 2 weeks, and another MRI was performed; this time the presence of a new nodular infiltration of the spine at the level of the L1 vertebral body  chemotherapy protocol for up to 8 cycles, every 21 days. The treatment was well tolerated with minimal side effects, mainly fatigue, headaches, and nausea. All the side effects responded well to symptomatic drugs. The patient is currently in complete remission with normal laboratory results except for slightly elevated AST (44 UI/L) and ALT (56 UI/L) levels which were considered secondary to therapeutic hepatotoxicity.3NSMM is a rare type of MM and is defined by the absence of detectable M protein in serum and urine. Two different subtypes of NSMM have been described. In the first subtype, the plasma cells produce immunoglobulins but are unable to release them out of the cell, probably due to decreased permeability, deficiency, or damage of intracellular light chains. This variant of NSMM is known as the “producer” type. The second form is the “non‐producer” type, in which immunoglobulin cannot be produced by plasma cells.The diagnosis of multiple myeloma is based on the presence of bone marrow plasmacytosis of >10%, monoclonal protein in serum and/or urine, as well as myeloma‐related organ dysfunction (CRAB criteria).Due to the absence of M protein in serum and urine, our patient did not meet the criteria for the diagnosis of MM but was labeled as an NSMM after the second MRI scan revealed a new bone lesion at the level of the L1 vertebral body, several other enlarged lesions (between 5 and 10 mm) within the “salt and pepper” marrow infiltration and confirmed by a positive bone marrow biopsy for plasmacytosis.This case emphasizes the importance of modern imaging (MRI) in the diagnosis of a rare form of multiple myeloma,Computed tomography (CT) is a sensitive method for the diagnosis of lytic lesions, but it is well known that patients with multiple myeloma present bone marrow infiltration before any lytic lesions can be seen on a CT scan,Modern imaging methods like MRI detect discrete marrow infiltration patterns before lytic lesions are detected on computed tomography and sometimes before the onset of any symptoms.On MR imaging, five different patterns of bone marrow infiltration in multiple myeloma were described. These patterns include a normal‐appearing marrow, focal infiltration, diffuse infiltration, and “salt‐and‐pepper”; the fifth pattern is a combination of focal and diffuse infiltrationThe “salt and pepper” infiltration of the bone marrow is seen in only about 3% of MM patients,If in doubt, chemical‐shift imaging is a fast and easy way to discriminate between normal bone marrow and malignant infiltration, and therefore, it should be included in routine MRI examinations of patients with suspected marrow infiltration.Another fast MRI technique to help differentiate malignant marrow lesions from benign marrow reconversion is the “functional” diffusion‐weighted (DWI) sequence and the corresponding apparent diffusion coefficient(ADC). ADC values in active myeloma are significantly higher than normal red or yellow marrow,In the case presented, the first spine MRI scan was performed in a private imaging clinic with a routine scanning protocol that included only T1, T2, and T2 fat saturation sequences; that is why the radiology report only pointed out the discrete “salt and pepper” pattern without a certain diagnosis of multiple myeloma infiltration. If further scan sequences like chemical shift imaging or DWI were performed, the radiologist's report would have been certainly more precise and the bone biopsy requested earlier.4Multiple myeloma (MM) is a plasma cell dyscrasia associated with the clonal proliferation of a defective plasma clone. Non‐secretory multiple myeloma (NSMM) is a rare variant of MM and accounts for less than 5% of all MM cases and often poses diagnostic difficulties. We present the case of a patient with NSMM who was diagnosed after a series of 2 spinal MRIs which showed bone marrow infiltration suggestive of MM . This case emphasis the need for different MRI sequences, to better discriminate between normal marrow reconversion and malignant infiltration.DC was involved in literature research and manuscript writing. HI was involved in critical feedback and manuscript revisions.No funding was received.The authors declare that there is no conflict of interest.Written informed consent was obtained from the patient for the publication of this case report.


Recent innovations in prophylactic treatment with steroids have overcome the issue of esophageal stricture after endoscopic submucosal dissection (ESD), except in entire circumferential esophageal squamous cell carcinoma (EC‐ESCC). Current Japanese guidelines weakly recommend performing ESD for clinical epithelial/lamina propria EC‐ESCC with a longitudinal extension <50 mm upon implementing prophylactic treatment against stricture. However, the accurate indications for ESD in EC‐ESCC remain unknown, and strategies differ among institutions. The aim of this study was to understand the initial treatment strategy for EC‐ESCC and prophylactic treatment after ESD against esophageal stricture.A questionnaire survey was conducted across 16 Japanese high‐volume centers on the initial treatment for EC‐ESCC according to the invasion depth and longitudinal extension, and prophylactic treatment against stricture.ESD was performed as the initial treatment not only in clinical epithelial/lamina propria lesions <50 mm (88–94% of institutions), but also in clinical epithelial/lamina propria ≥50 mm (44–50% of institutions) and clinical muscularis mucosae/SM1  lesions <50 mm (56–75% of institutions). Regarding prophylactic treatment against esophageal stricture, although there was a common point of local steroid injection, the details and administration of other treatments varied among institutions.As ESD was performed with expanded indications for EC‐ESCC than those recommended by the guidelines in more than half of the institutions, the validity of ESD for expanded EC‐ESCC needs to be clarified. For that, it is necessary to prospectively collect short‐ and long‐term outcomes after ESD and other treatments, including esophagectomy or chemoradiotherapy. In recent times, a large number of early esophageal squamous cell carcinomas (ESCCs) are treated with endoscopic submucosal dissection (ESD) worldwide. Esophageal stricture is known to be a crucial problem, especially in cases with post‐ESD mucosal defects larger than three‐quarters of the circumference of the esophageal lumen, when no prophylactic treatment to prevent stricture is administered.Esophagectomy or definitive chemoradiotherapy (CRT) is generally recommended for cT1 ESCC if ESD is not performed.There are no reports on the initial treatment selection for superficial EC‐ESCC according to the lesion's invasion depth and longitudinal extension in real clinical practice. Also, little is known about the current status of the prophylactic treatment against stricture after ESD of EC‐ESCC although there were some reports from high‐volume centers.This was a questionnaire survey of 16 Japanese high‐volume centers all over Japan, which are recognized as the training facilities for certified fellows of endoscopists by the Japan Gastroenterological Endoscopy Society and the major referral institutions treating a large number of esophageal cancers  used oral steroids, regardless of the longitudinal extension of the lesion Figure . The varProphylactic endoscopic balloon dilation (EBD) was used in a few institutions (7%–19%), and this did not depend on the longitudinal extension of the lesion. In addition, one institution used polyglycolic acid sheets as a prophylactic treatment.The treatment strategy for esophageal stricture after ESD was requested Table  and Q4. In this multi‐institutional questionnaire study, we demonstrated that ESD was performed with expanded indications for EC‐ESCC than those recommended by the ESD/EMR guidelines in more than half of the institutions surveyed. Regarding the prophylactic treatment against esophageal stricture, although there was a common point of local steroid injection, the details of local steroid injection and other treatments varied between institutions. As for the treatment of esophageal stricture after ESD, although EBD was the main treatment, RIC was also performed in half of the institutions for refractory stricture.The results of this questionnaire indicated that the initial treatment strategy for EC‐ESCC remains controversial. This is because of the lack of short‐ and long‐term outcomes data for each treatment. In particular, there are several diagnostic and therapeutic factors that may suggest that ESD should not be performed for lesions of the entire circumference. The invasion depth of EC‐ESCC is more difficult to diagnose than that of non‐entire circumferential ESCC, and relatively high non‐curative resection rates (17%–39%)Local steroid injection and oral steroid administration are mainly used for prophylactic treatment of esophageal stricture after ESD; however, the details have not yet been determined. Therefore, the superiority of oral steroid administration in terms of stricture‐free survival over local steroid injection therapy after ESD is currently being evaluated in patients with ESCC in a phase III randomized controlled trial (JCOG1217).Although there have been many previous reports on the treatment for esophageal stricture after esophagectomy for ESCC, there are few reports focusing on esophageal stricture after ESD. It is well known that the length of stricture after ESD is longer than that after esophagectomy, and stricture after ESD is considered to be more severe than stricture after esophagectomy, with a higher refractory stricture rate and a longer time to relief from stricture.This study has several limitations. First, this multi‐institutional questionnaire targeted expert endoscopists in a high‐volume center. A high volume of referral hospitals that participated in this survey have several specialists containing surgeons, advanced endoscopists, medical oncologists, and radiation oncologists and they can communicate about patients’ treatment strategies through the cancer board. Although patients with esophageal cancer tend to be treated in high‐volume centers in Japan, the generalization of our results into general hospitals can be one of the limitations of our study. Second, this multi‐institutional questionnaire did not focus on the complications of prophylactic treatments as we did not have access to patients’ clinical information. Therefore, we could not compare each prophylactic treatment. Third, there were no survey items related to surgery or CRT, and we could not compare the advantages and disadvantages of the initial treatment. Finally, as this study was a questionnaire survey, we did not assess the clinical outcomes and prognosis after ESD and after prophylactic treatment against stricture. To overcome these limitations, a multicenter prospective study is required. Hence, a prospective observational study  that evaluates the clinical course after ESD, surgery, and CRT for superficial EC‐ESCC is currently being conducted by our group.In conclusion, in this multi‐institutional questionnaire study, in more than half of the institutions, ESD was performed with expanded indications for EC‐ESCC lesions than those recommended by the ESD/EMR guidelines. In addition, the details of prophylactic treatment against esophageal strictures varied among institutions. Thus, a prospective study collecting the short‐ and long‐term outcomes after each treatment  is needed to clarify these outcomes.Co‐authors Seiichiro Abe and Waku Hatta are associate editors of DEN Open. The rest of the authors declare no conflict of interest.


To perform endoscopic sinus surgery safely and effectively, surgeons need to visualize the complex anatomy of the anterior ethmoid and frontal sinus region. Because this anatomy is so variable and individualized, the foundation of understanding lies in identifying, following, and visualizing the drainage pathway patterns and anticipating possible variations.We studied 100 sides  using computed tomography (CT) and multiplanar reconstruction (MPR) to identify and classify the drainage pathways leading to the frontal sinus and anterior ethmoidal cells.Analysis revealed five patterns of drainage pathways defined by their bony walls: between the uncinate process and the lamina papyracea [UP–LP]; between the uncinate process and the middle turbinate [UP–MT]; between the uncinate process and the accessory uncinate process [UP–UPa]; between the uncinate process and the basal lamella of the ethmoidal bulla [UP–BLEB]; and between the basal lamella of the ethmoidal bulla and the basal lamella of the middle turbinate [BLEB–BLMT]. In most cases, BLEB formed the posterior wall of the drainage pathway of the frontal sinus, indicating BLEB could be one of the most important landmarks for approaching the frontal sinus.As endoscopic sinus surgery depends on an understanding of this anatomy, this study may help surgeons to identify and follow the drainage pathways more accurately and safely through the anterior ethmoid to the frontal sinus. The anatomy of the anterior ethmoid and frontal sinus is complex, but improvements in imaging technology are helping us to understand these spaces more clearly. Many recent reports have identified and classified the cells of the anterior ethmoid and frontal sinus based on their location –5. HowevIn our study, the drainage pathways are formed by some combination of two of the following: the middle turbinate (MT), the basal lamella of the middle turbinate (BLMT), the uncinate process (UP) and its variations (UPa), the basal lamella of the ethmoidal bulla (BLEB), and the lamina papyracea (LP). We followed each drainage pathway to its termination as a cell  or as a frontal sinus . The frontal sinus was determined based on location and size. Rather than focusing on cells, this study identifies the drainage pathways themselves to improve our understanding of the anatomy of the anterior ethmoid and frontal sinus.© was used for three-dimensional (3D) and multiplanar reconstruction (MPR). CTs were obtained from June 2020 through October 2020 from 100 sides . Exclusion criteria included previous sinus surgery or the presence of sinusitis. Inclusion required confirmation of drainage pathways to the frontoethmoidal region.Axial computed tomography (CT) scans were performed on Toshiba Alexion TSX-032A CT scanner using 1 mm thickness. InVesaliusTo begin identification of a drainage pathway, we started in the middle meatus and followed the drainage pathway formed by the bony walls of the anterior ethmoid to its termination, which might be the frontal sinus or an anterior ethmoidal cell or cells. Anterior ethmoidal cells included any frontal cells at the transition from ethmoidal to frontal bone, not including the frontal sinus. The word “cell” in this paper may refer to a pneumatized DP or a terminal recess; these are difficult to differentiate. We considered the frontal sinus to be the largest cell in contact with the squamous portion of the frontal bone.In the “fronto-ethmoidal transition region,” coined by Zinreich et al., it can be difficult to distinguish between the uncinate process and the basal lamella of the ethmoidal bulla because of the labyrinthine nature of the ethmoidal complex . We usedAfter we had identified and named the five drainage pathway patterns, we calculated the prevalence for each pattern with 95% confidence interval (CI). Table Note: For the figures, we selected 5 sides out of 100 total sides, both right and left. However, to reduce confusion and improve consistency, we inverted any left sides so that all figures appear as right sides.For example:[UP–LP] denotes the drainage pathway.[UP–LP- > FS] denotes the drainage pathway leading to a frontal sinus.[UP–LP- > C] denotes the drainage pathway leading to a cell or cells.[UP–LP] between uncinate process and lamina papyracea[UP–LP] was found in 100 sides. [UP–LP- > FS] was found in 11 sides. [UP–LP] occurred in all sides, because it is analogous to the ethmoidal infundibulum (EI). [UP–LP- > C] began at the junction of UP and FPM (the inferiormost agger nasi) and expanded upwards along FPM and LP from EI  of FS in 100 sides, likely due to the stability of attachment of UP and MT to FPM.Consistent with Jiang et al., we observed a few cases of UPa anterior to BLEB, distinct from UP and connected to FPM . [UP–UPa[UP–BLEB] forms from the anterior surface of BLEB, where the posterior margin of UP connects to BLEB forming the suprainfundibular plate. As noted earlier, unlike the other DPs, [UP–BLEB] tends to form a narrow opening as it is compressed by its lamellae. Pianta et al. describe a singular FSDP dividing the “agger complex” (between FPM and FSDP) and the “bullar complex” (between the FSDP and BLMT), which corresponds roughly to [UP–BLEB] . However[BLEB–BLMT] may be referred to as the superior semilunar hiatus. [BLEB–BLMT] forms cells between BLEB and BLMT. The cell formed posterior to the transition between ascending and descending crus of BLEB is called the ethmoidal bulla. In our study, [BLEB–BLMT] could form up to three cells, each from a separate branch, with a multilayered structure posterior to BLEB.posterior wall of the drainage pathway (Fig. There is a critical difference between [BLEB–BLMT- > FS] and the other four drainage pathways. In [BLEB–BLMT- > FS], the anterior margin of BLEB connects to FPM, with BLEB forming the anterior wall of [BLEB–BLMT]. In contrast, in [UP–LP- > FS], [UP–MT- > FS], [UP–UPa- > FS], and [UP–BLEB- > FS], the anterior margin of BLEB connects to the skull base, forming the way Fig. . There aIn our study, 95% of the FS drainage pathways were anterior to BLEB; in almost all sides, the anterior margin of BLEB connected to the skull base to form the posterior wall of the drainage pathway. Therefore, BLEB, along with UP, may be the most important landmark for approaching the frontal sinus.We are aware of the limitations of this study. Further study to assess interrater agreement may be necessary to address the possibility of familiarity bias. In addition, the CTs were from healthy subjects whose anatomy was free of bony remodeling. All of the subjects were Japanese; a more heterogeneous study population might reveal different results .We believe, however, that this paper may clarify some issues related to the complex anatomy of the drainage pathways of the frontoethmoidal region: the developmental pathways leads to understanding of the drainage pathways, and the drainage pathways guide the surgeons through the anterior ethmoid to the frontal sinus.Beginning in the middle meatus and following the drainage pathways, which themselves follow the developmental pathways, leads us to the cells and sinuses of the frontoethmoidal region. We hope this paper will help other surgeons to perform ESS more safely through a better understanding of the drainage pathways of the frontoethmoidal region.