Since self‐healing of cementitious materials can theoretically improve the service‐life of concrete structures, it has gathered significant attention from both researchers and industry during the last two decades. Many researchers have proposed different methods to assess and quantify the self‐healing capacity  that is generated in concrete autogenously as well as autonomously. Even though many methodologies can be found in the literature, a way to accurately quantify the healing products produced by any self‐healing mechanism has not been yet achieved. In this study, a methodology is proposed to observe and to quantify in‐time formation of healing products based on active thin sections. Thin sections of Portland cement paste have been prepared with no epoxy impregnation to facilitate reactions between the cement matrix and the surrounding environment. Artificial cracks (260 μm wide) were induced at 28 days of age and the crystal growth was continuously monitored up to 28 days of self‐healing. Through image analysis of the micrographs, it was calculated that the autogenous self‐healing capacity of paste (triggered by portlandite carbonation in uncontrolled indoor conditions) was around 55% after 28 days of self‐healing. Healing products were further characterised through Environmental Scanning Electron Microscope analysis. Based on the results obtained in this study, the proposed methodology seems to be promising to compare the self‐healing mechanisms triggered by different healing agents. Due to the relatively low tensile strength of concrete, cracks are an unavoidable phenomenon affecting concrete structures during their service life. However, concrete has an intrinsic autogenous ability to heal cracks.To investigate the occurrence of the autogenous self‐healing mechanism and that induced by different agents, many methods have been proposed in the literature. Currently, the self‐healing capacity of engineered cementitious materials is generally assessed by two main methods, which are based on observing crack closure during time and by evaluating the recovery of functional properties of interest (i.e. water tightness).2w/c) of 0.50. Paste cylinders of 20 mm in diameter and 35 mm high were cast in plastic moulds, sealed with plastic foil and kept hydrating in a high humidity chamber (RH > 95%) for 28 days. At 28 days of hydration, the specimens were de‐moulded and thin sections were prepared as schematically represented in Figure To evaluate the feasibility of analysing self‐healing capacity of cementitious materials through active thin sections, Ordinary Portland cement paste specimens were prepared with a water/cement ratio  and then quantified through ‘Analyze’ tools of the freeware ImageJ. The self‐healing capacity (SHC) of the active thin section was calculated as follows (1):iA is the area of the crack as soon as it was induced [mm2] and A28d is the remaining area of the crack at 28 days of self‐healing incubation [mm2]. As a proof of concept, only a limited portion of the whole crack was analysed through this method in the present study.The specimens were sawn perpendicularly to their height to obtain about 5 mm thick paste disks. The two faces of the cylindrical disks were glued to a glass object holder with UV activated glue. After glue hardening, the disks were sawn at their middle height with a 2 mm thick sawing blade. As a consequence, two disks of around 1 mm thick could be obtained out of each cylinder. Using a ‘Struers SystemAbele’ grinding machine, the thickness of the disks was firstly manually reduced to around 200 μm with a 125 μm diamond plate and then it was brought to 30–50 μm through a 35 μm diamond plate. Ethanol and water‐free liquids were used during the entire sawing and grinding procedure. Once a thickness of about 30–50 μm was obtained, artificial cracks were introduced by running a high‐precision micro dicing saw  over the thin section. The width of the artificial cracks was the same as the sawing blade thickness, which was around 260 μm. Micrographs of the initial state of the thin sections were acquired by stereomicroscopy . To trigger the self‐healing mechanism of cement, thin sections were kept exposed to the atmosphere in a high‐humidity chamber (RH>95%) and they were examined after 28 days. The samples were not isolated from the surrounding environment in order to facilitate acceleration of the self‐healing mechanism triggered by the interaction with CO3A typical self‐healing capacity of Portland cement paste can be visually observed by the active thin sections, as presented in Figure At 0 days of self‐healing incubation  micrographs of portions of the healed thin sections . The apparent good agreement between micrographs taken with the light microscope and the SEM allow to conduct image analysis for SHC quantification of the former ones, which detrimentally reduces the time of the experimental quantification. The degree at which the SHC results are sensitive to the micrographs that are considered will be quantitatively addressed in future studies.4In this study, we proposed a methodology to evaluate and assess the self‐healing capacity of cementitious materials. As a proof of concept of this methodology, we evaluated the self‐healing mechanism of plain Portland cement paste triggered by carbonation in uncontrolled indoor conditions. Through microscopy and image analysis, a SHC equal to around 55% for a 260 μm wide crack after 28 days of self‐healing incubation was obtained. Through active thin sections, the autogenous self‐healing of cement paste due to carbonation can be observed and quantified during time non‐destructively. Theoretically, this methodology could be extended to observe self‐healing mechanisms of cementitious materials stimulated by embedded agents .2. However, to observe the results of self‐healing due to added‐in agents only, isolation of the sample from the surrounding must be ensured. This might be achieved, among other methods, by placing a cover glass at the top of the section and isolating the glass sides, leaving a gap in the proximity of the crack mouth only. Also, keeping the section submerged in water would deny CO2 from reaching the sample surface. However, in this case the resulting SHC might be reduced since some healing agents (e.g. bacteria‐based ones) need the presence of O2 to be effective. Hence, more research on the applicability of active thin sections to evaluate stimulated self‐healing as well as comparing the efficiency of different engineered systems is in progress. However, based on the above‐mentioned characteristics of this method, applying active thin sections to evaluate the SHC of engineered self‐healing materials might bring valuable information, such as the 2D quantification of in‐time produced crystals as well as the locations at which these crystals precipitate.When quantifying the SHC of engineered cementitious materials with currently available methodologies, it is always difficult to differentiate between the amount of healing products produced by any interaction with the surrounding environment and that triggered by the embedded healing agents. This differentiation would help to better evaluate the efficiency and actual SHC of the proposed systems. In the present proof of concept, no cover glass was placed at the top of the active thin section to facilitate the interaction between the matrix and the surrounding COIt is worth mentioning again that the proposed methodology involves the preparation of thin sections subjected to cutting, grinding and polishing without prior embedding the sample in epoxy. Even though all the preparation steps have been conducted to minimise any potential contamination of the sample, particle pull‐outs, micro‐cracking and other artefacts are likely inevitable. For these and other reasons , it might be that the self‐healing capacity measured through this method differs from the actual performance of the material exposed to different conditions or with different configurations. Nevertheless, this methodology could still be useful to observe some (still unclear) aspects related to the self‐healing mechanism of cementitious materials, such as the micro‐scale morphology of the growing crystals as well as the locations and conditions at which they get formed most likely. To this aim, further research is needed and is currently ongoing.


Fatigue is common following aneurysmal subarachnoid haemorrhage (aSAH) but little is known about its frequency, prognosis and impact on employment. The aim of this study was to assess the frequency of fatigue, whether it changes over time and the relationship to employment in the long term.This was a retrospective observational study of aSAH cases and matched controls from the UK Biobank. The presence of fatigue was compared between cases and controls using the chi‐squared test. The change in frequency over time was assessed using Spearman's rank correlation coefficient. The effect of fatigue on employment was assessed using mediation analysis.χ2 = 13.0, p < 0.001) at a mean follow‐up of 123 months. Fatigue gradually improves over time with significant fatigue decreasing by 50% from ~20% in the first year to ~10% after a decade (p = 0.04). Fatigue significantly mediated 24.0% of the effect of aSAH status on employment.Fatigue is more common following aSAH compared to matched controls (aSAH 18.7%; controls 13.7%; Fatigue is common following aSAH and persists in the long term. It gradually improves over time but has a major impact on aSAH survivors, significantly contributing to unemployment following haemorrhage. Further work is required to develop treatments and management strategies for fatigue with a view to improving this symptom and consequently employment following aSAH. Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating form of stroke associated with significant morbidity and mortality. It affects younger people than other stroke types, resulting in a disproportionately high socio‐economic impact due to loss of productive employment and the long‐term healthcare burden . SurvivoFatigue is another common consequence of aSAH with one analysis reporting a weighted mean fatigue frequency of 73.6% in the first year, falling to 50.7% thereafter, based on five published studies [Fatigue has significant implications for patients and has been associated with reduced quality of life and impaired return to work following aSAH , 8, 9. AThe aim of this study was (i) to assess the frequency and phenotype of fatigue in the long term following aSAH; (ii) to identify whether the frequency of fatigue changes over time; and (iii) to assess whether fatigue mediated any of the effect of aSAH on employment status.This was a retrospective case–control study using data from the UK Biobank, a major biomedical database . This stFatigue was assessed in the UK Biobank at assessment centre visits using the question ‘Over the past 2 weeks, how often have you felt tired or had little energy?’ (data field 2080). Individuals were categorized as suffering significant fatigue if they reported tiredness or little energy for more than half the time. A subset of individuals answered questions about fatigue phenotype Table , scored Aneurysmal subarachnoid haemorrhage cases were identified from the UK Biobank using International Classification of Diseases (ICD) 9 (data field 41271), ICD‐10 (data field 41270), self‐reported medical conditions (data field 20002) and primary care data (data field 42040). Individuals were excluded if the subarachnoid haemorrhage was non‐aneurysmal in nature or if there was a trauma code documented within 30 days of diagnosis .A total of 869 aSAH cases were identified from the UK Biobank. 829 were eligible for inclusion with data available on fatigue. 479,617 individuals were eligible for inclusion in the control cohort and 3316 controls were matched with a mean standard difference <0.004  at a mean follow‐up of 123 months. Length of stay and hydrocephalus were not significant predictors of fatigue following aSAH in this cohort . After correction for multiple testing four fatigue phenotypes were more significant in the aSAH cohort compared to controls: ‘fatigue interferes with work, family or social life’, ‘fatigue is amongst the three most disabling symptoms’, ‘fatigue causes frequent problems’ and ‘easily fatigued’ . Mediation analysis identified that the estimated natural indirect effect of aSAH status on employment that was mediated by fatigue was significant, with an odds ratio of 1.21 . The odds ratio for the estimated natural direct effect of aSAH status on employment was 2.97 . The proportion of the effect of aSAH on employment mediated by fatigue was 24.0%.Unemployment or inability to work due to sickness/disability was significantly more frequent in the aSAH population . The proportion of the effect of aSAH on employment mediated by headache was 8.3%.By comparison the estimated natural indirect effect of aSAH status on employment that was mediated by headache was significant, with an odds ratio of 1.06  was used to assess frequency of fatigue. Future prospective studies should use more detailed assessments of fatigue, including validated tools such as the Chalder fatigue scale  or the fFinally, in this analysis, data were only available on employment status following aSAH and consequently it was not possible to study change in employment status before and after aSAH. This finding needs to be confirmed using employment data from individuals before and after aSAH.Fatigue is more common following aSAH compared to matched controls and persists in the long term. Fatigue gradually improves over time with significant fatigue decreasing by about 50% from around 20% in the first year to 10% after a decade. Fatigue negatively impacts quality of life and employment following aSAH. Further work is required to develop treatments and management strategies for fatigue following aSAH with a view to improving quality of life and employment.IG and DB conceived the study. All authors contributed to the study design. The first draft of the manuscript was written by BG and HC; all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.BG is funded by the Royal College of Surgeons of England, Society of British Neurological Surgeons, Barrow Foundation and Guarantors of Brain in addition to the Institute for Life Sciences, University of Southampton.None.Table S1Click here for additional data file.


COVID‐19 disease‐related coagulopathy and thromboembolic complication, an important aspect of the disease pathophysiology, are frequent and associated with poor outcomes, particularly significant in hospitalized patients. Undoubtedly, anticoagulation forms a cornerstone for the management of hospitalized COVID‐19 patients, but the appropriate dosing has been inconclusive and a subject of research. We aim to review existing literature and compare safety and efficacy outcomes of prophylactic and therapeutic dose anticoagulation in such patients.We did a systematic review and meta‐analysis to compare the efficacy and safety of prophylactic dose anticoagulation when compared with therapeutic dosing in hospitalized COVID‐19 patients. We searched PubMed, Google Scholar, EMBASE and COCHRANE databases from 2019 to 2021, without any restriction by language. We screened records, extracted data and assessed the risk of bias in the studies. RCTs that directly compare therapeutic and prophylactic anticoagulants dosing and are not placebo‐controlled trials were included. Analyses of data were conducted using the Mantel–Haenszel random‐effects model . The study is registered with PROSPERO (CRD42021265948).I2 –0%], whereas major bleeding as an adverse event was found lower in prophylactic anticoagulation in comparison with therapeutic anticoagulation that was statistically significant .We included three studies in the final quantitative analysis. The incidence of thromboembolic events in therapeutic anticoagulation was lower in comparison with prophylactic anticoagulation in hospitalized COVID‐19 patients and reached statistical significance [RR 1·45, 95% CI  Our study shows that therapeutic dose anticoagulation is more effective in preventing thromboembolic events than prophylactic dose but significantly increases the risk of major bleeding as an adverse event. So, the risk–benefit ratio must be considered while using either of them. Therapeutic dose anticoagulation is more effective in preventing thromboembolic events than prophylactic dose but significantly increases the risk of major bleeding as an adverse event. So, the risk–benefit ratio must be considered while using either of them. Many observational studies have shown the rationale for both therapeutic and prophylactic doses of anticoagulation with low molecular weight heparin (LMWH) to reduce morbidity and mortality in these patients.In this systematic review and meta‐analysis, we aim to summarize the safety and efficacy of prophylactic anticoagulation against therapeutic anticoagulation in patients hospitalized with COVID‐19. Some randomized controlled trials (RCTs) are performed comparing the safety and efficacy of either in patients with COVID‐19 infection, but there was an urgent need for systematic review and meta‐analysis to make the conclusions more robust.22.1This study was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement.We performed a systematic search of RCTs comparing the outcome of prophylactic and therapeutic anticoagulants in hospitalized COVID‐19 patients. PubMed, EMBASE and COCHRANE were the online databases used to search for studies. We utilized Google Scholar and reference of other manuscripts to search for additional studies. We developed a search strategy and adjusted it for each engine using different keywords: prophylactic anticoagulation, therapeutic anticoagulation AND (COVID‐19 OR coronavirus OR coronavirus disease OR coronavirus disease‐19 OR severe acute respiratory syndrome OR SARS‐CoV‐2). The exact search strategy used in one of the databases (PubMed) is provided as a supplementary file. The references of the included studies were reviewed to search for additional studies. Databases were searched on 7 July 2020, and there were no language restrictions applied during the search, screen or the selection process of studies. The included studies were published between 2019 and 2021. This systematic review and protocol were registered online in PROSPERO (CRD42021265948).2.2Randomized controlled clinical trialsComparing therapeutic versus prophylactic anticoagulation in COVID‐19 patientsPatients may be critically or non‐critically illInclusion criteriaOther study types except for RCTsExclusion criteriaWe developed inclusion and exclusion criteria for the studies as follows:Based on the aforementioned criteria, title and abstract screening were done by two independent reviewers [Robin Rauniyar (RR1) and AM] using Covidence. The third reviewer (SK) reviewed all the studies of conflict. The full‐text review of studies qualifying inclusion criteria after the title and abstract screening was done by another reviewer [Rohit Rauniyar (RR2)].2.3Two authors [SY and Rahul Rauniyar (RR3)] independently extracted the data in MS Excel version 2016. An Excel sheet template was made, and data were extracted under the following heading: author name, study year, number of participants and study design. Under each study, treatment and control arms were made, and safety and efficacy outcomes were extracted and recorded. Safety outcome of concern included the occurrence of major bleeds, and the efficacy outcome was the occurrence of thromboembolism . The extracted data were again reviewed by another reviewer (ST).The qualities of RCTs were assessed by two authors (RR1 and ASN) using the Cochrane Risk of Bias Tool.2.4I2 statistic).Pooled proportions, risk ratio (RR) and 95% confidence intervals of safety and efficacy outcomes were generated from included RCTs. Forest plots of comparative RRs (prophylactic vs. therapeutic) were created using the RevMan 5·4 software. Analyses were conducted using the Mantel–Haenszel random‐effects model .33.1A total of 804 studies were identified on initial search on different databases, of which 15 duplicates were removed. After title and abstract screening of 789 studies, seven studies were eligible for full‐text review. Finally, a total of three RCTs were included in our systematic review and meta‐analysis. The study review process is depicted in the PRISMA flow diagram  included in our study was 1732.The total number of participant patients in the RCTs  3.3I2 –54%]   I2 –54%3.4Results from the quality assessment are provided in the table below. All the studies included did not report on allocation concealment and blinding of participants and personnel. All studies used random sequence generation and reported on blinding of outcome assessment. None of the studies reported incomplete outcome data, and no evidence of selective reporting was found in any studies Figure .4The consensus guideline suggests the usage of parenteral LMWH for thromboprophylaxis in COVID‐19.The prevalence of arterial or venous thromboembolism (VTE) in hospitalized COVID‐19 patients varies widely, ranging from 15.2% to 69% among different studies.p = 0.029).There have been many proposed treatments for the COVID‐19 patients, of which remdesivir, hydroxychloroquine, steroids and anticoagulants have been studied the most. So far only dexamethasone has been shown to have 28‐day mortality benefit in COVID‐19 patients in the RECOVERY trial.n = 20) in the trial hampers the confidence of its results.Our meta‐analysis shows that the therapeutic dose anticoagulation has better efficacy that was statistically significant in terms of prevention of occurrence of thrombosis when compared with prophylactic dose. Similarly, our safety outcome measured in terms of major bleeding episodes suggests that prophylactic dosing has a lower incidence of major bleeding as an adverse event that reached statistical significance when compared directly with therapeutic dosing. The major bleeding described in the RCTs is per the definition of the International Society on Thrombosis in which major bleeding in non‐surgical patients is defined as having (1)fatal bleeding, and/or (2)symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra‐articular or pericardial or intramuscular with compartment syndrome, and/or (3) bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells. These findings are consistent with a recent systematic review that aimed to explore the association between therapeutic dose anticoagulation and its effect on mortality in COVID‐19 patients. It summarized the findings of nine studies, among which three retrospective cohort studies reported a reduction in the mortality rate, while six other studies showed no mortality benefits among COVID‐19 patients treated with therapeutic dose of anticoagulation.Although this review and meta‐analysis tries to solve the clinical question of appropriate dosing of anticoagulation in COVID‐19 patients, there is still a need for other RCTs directly comparing the two arms with appropriate outcomes. This study supports the use of therapeutic dose anticoagulation over prophylactic dose due to its significant decrease in the occurrence of thrombosis as an efficacy outcome, but there is a significantly increased incidence of major bleeding as an adverse event with therapeutic dose of anticoagulants. So, there must be a risk–benefit analysis before using either of the doses considering the comorbid conditions, which might increase the propensity of bleeding.n = 20).I2 54%; we used random‐effects model to analyse the pooled result, but leave‐one‐out study analysis could not be performed due to limited number of studies included in the analysis. Also, the exact dose of anticoagulant used as prophylactic and therapeutic dose in COVID‐19 patients have not been mentioned in all the RCTs included in our review.The major strength of this systematic review and meta‐analysis is that only RCTs have been included in the quantitative analysis, so the strength of association could be accurately measured. Similarly, the included RCTs directly compare therapeutic and prophylactic dosing and are not placebo‐controlled trials that give better strength of evidence. The major limitation of our study is the number of RCTs included, and heterogeneity in the number of participant patients in the included trials as one of the RCTs included a small number of patients (The authors declare no competing interests.Robin Rauniyar (RR1), Sandip Kuikel (SK), Aman Mishra (AM), Rohit Rauniyar (RR2) and Rahul Rauniyar (RR3) designed the study. RR1 and Shikha Yadav(SY) designed and ran the literature search. Sahil Thapaliya (ST) and AM performed the title and abstract screening. The conflicts were resolved by Amit Sharma Nepal(ASN). The full‐text review was done by RR2. RR1 and RR3 extracted the data and analysed them. RR3 assessed the risk of bias. RR1, SK and AM wrote the manuscript. All authors provided critical conceptual input, analysed and interpreted data and critically revised the report.


Ageing is characterized by physiological characteristics as the part of natural lifespan and by pathological healthspan processes in response to stress, environmental changes, and diseases. Ageing is a pattern of morphological and functional decline of cells in tissues and circulation, that is correlated with the genetic backgrounds of individuals and with molecular regulatory pathways that may resist ageing influences. The discovery and development of interventions for molecular and cellular rejuvenation is a new and revolutionary field of clinical and translational medicine. Understanding the genetic and epigenetic mechanisms by which health span and lifespan can be regulated, manipulated, and extended is important for identifying and validating “rejuvenating interventions”. These mechanisms include signal regulation, metabolic interference, reprogramming, heterochronic parabiosis, target‐based drugability, and senescent editing.Potential targets for influencing ageing are systemic and local metabolic disorders that occur gradually during the ageing process. For example, Melatonin is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism that interferes with cell proliferation and growth and induces apoptosis by regulating carboxylesterase 1 expression and epigenetic modification, lipid droplet accumulation, endoplasmic reticulum stress, de novo androgen synthesis.It is a challenge to discover and develop ageing specific biomarkers in the circulation on basis of the metabolites from ageing cells as well as to validate and translate those measurable molecules for clinical practice implementation. Contents of ω‐3 polyunsaturated fatty acids in the human retina play decisive roles in the maintenance of retinal structure and function, and metabolism, and potentially prevent age‐related macular degeneration. Because it is not possible to directly measure retinal ω‐3 content, Acar et al. in the Biomarkers of Lipid Status and Metabolism in Retinal ageing project (2021) assessed lipidomic profiles in the circulation and developed a prediction model to evaluate the predictive strength for determining retinal ω‐3 content.2+ influx into the cytoplasm to induce autophagy and NRF2 activation.4+and CD8+ T cells and B cells.The development of natural molecules‐based interference and lifestyle‐associated reprogramming are considered potential approaches to prevent and treat ageing‐associated dysfunction and diseases. Cell senescence is an important process of cell growth arrest that is dependent upon cellular replication with telomere attrition or stress degrees and is associated with the development of ageing‐related susceptibility and diseases. Of potential therapeutic approaches, the ginsenoside Rg3 (Rg3) was found to have anti‐senescent activity by targeting the calcium release‐activated calcium modulator 1 (ORAI1) protein and activating the adenosine 5‘‐monophosphate (AMP)‐activated protein kinase to promote CaWith rapid development, scRNA‐seq has been widely applied for detecting intercellular heterogeneity and communication, clustering new cell populations in cancer, inflammation, chronic diseases, and ageing. Pálovics et al. investigated inter‐organ and inter‐cellular heterogeneity of transcriptomic profiles in response to heterochronic parabiosis, an approach to exchange blood from young to old or vice versa, and provided solid evidence and new insights for understanding systemic responses and molecular networks among blood‐borne factors and cells at the single‐cell solution.In conclusion, understanding ageing and rejuvenating interventions are one of critical processes of clinical and translational medicine. Understanding the complexity of molecular metabolisms, immune responses, and genetic regulations will be important for the discovery and development of ageing‐associated biomarkers and therapeutic targets. Transcriptomic patterns of circulating immune cells, red blood cells, and platelets at single‐cell resolution can be an important window to examining molecular mechanisms of ageing initiation and development. To translate scRNA‐seq to clinical application, a deep understanding of ageing and rejuvenation from clinical observation to the single‐cell solution will provide opportunities for the innovation and development of new therapeutic strategies.The authors declare that they have no competing interests.


COVID‐19 rapidly transformed how Australians access health care services. This paper considers how the inability for urban patients to access in‐person care expediated the introduction of virtual solutions in health service delivery thus creating a new access paradigm for rural and remote Australians.in real terms the distance from, and therefore the time taken to access, critical public services. ‘Lockdowns’ have unlocked health access for rural and remote Australians in ways that had been rejected prior to 2020. The pandemic has disrupted traditional delivery models and allowed the piloting of novel solutions, at the same time as stress‐testing current delivery systems. In the process, it has laid bare a myopia we term ‘urban paternalism’ in understanding and delivering rural health.‘Physical distancing’ is a phrase synonymous with public health responses to COVID‐19 in Australia, but distance is a decades‐long problem for rural health access. Counterintuitively, the pandemic and associated restrictions on mobility have reduced This commentary outlines how the COVID‐19 operating environment has challenged traditional urban‐dominated policy thinking about virtual health care delivery and how greater availability of telehealth appointments goes some way to reducing the health access gap for rural and remote Australians.Australian Commonwealth Government policy changes to expand the Medical Benefit Scheme (MBS) to include telephone or online health consultations are a positive initiative towards supporting Australians through the ongoing public health crisis and have also created access parity for some rural and remote patients. Although initially announced as a temporary COVID‐19 measure in March 2020, telehealth has now become a permanent feature of the Medicare landscape. This significant public health reform has paved the way for a more flexible and inclusive universal health care system but, more importantly, taken much needed steps towards improving access to primary health care for patients in rural and remote areas. Now the question is: Can the health care system integrate this virtual model of delivery into ‘business as usual’ to ensure the long‐term sustainability of telehealth services to rural and remote Australia? Physical access to timely, reliable and quality clinical care is not guaranteed for people living in rural and remote communities in AustraliaDigital health technology was not widely employed in rural and remote Australia pre‐pandemicThe pandemic had unintended positive consequences in forcing greater flexibility into health delivery systemsApproaches that had previously been resisted, were embraced, and resulted in the levelling of some health access deficits in rural and regional AustraliaNow that measures to increase flexibility in delivery of health beyond the traditional face‐to‐face model have been proven effective, further reform of primary health care delivery needs to be investigated and implemented1Physical distancing and lockdowns became part of the lexicon of coronavirus disease 2019 (COVID‐19) and public health in 2020.In this paper we define ‘access’ in terms of timeliness and affordability for the health consumer. The consequence of poor health access is the unequal distribution of opportunity and lowered health outcomes.2An unconscious form of metropolitan bias has dominated the Australian health landscape for decades.urban paternalism flourishes. Paternalism is characterised by people in authority regulating policy or practices in their own interest. The Macquarie Dictionary defines paternalism as ‘the principle or practice, on the part of a government or of any body or person in authority, of managing or regulating the affairs of a country or community, or of individuals, in the manner of a father dealing with his children, especially to the extent that individual rights are abrogated, such as freedom of choice and individual responsibility’.In fact, Australia is one of the most urban‐developed nations in the world.3An unexpected outcome from COVID‐19 was the rapid expansion of telehealth. Telehealth services include virtual care via ‘video communication, remote consultation, telephonic videos, remote monitoring, provider‐to‐provider communication, apps and Web‐based platforms’.4Telehealth had been used relatively sparingly in rural and remote health delivery where in‐person delivery of health was impracticable.Regardless of the motivations, this pandemic‐driven paradigm shift to large‐scale uptake of remote consultations has led to tangible health access gains, particularly in rural and remote settings. First driven by this emergency, customisable software systems and off‐the‐shelf technologies are now embraced and breaking down access barriers.5The need for face‐to‐face delivery of certain health‐related procedures and tests has not changed—but a willingness to support virtual consultations through the MBS has dramatically increased. Policy change has strengthened the role of telehealth services in Australia's health care industry, marking a more inclusive way to meet patients' basic needs across the nation. However, these changes were only ever meant to last the duration of the crisis, the implementation of which policy‐makers viewed as a short‐term stop gap.6All Australians, and in particular rural Australians, are well positioned to become long‐term beneficiaries of the COVID‐19‐driven reform of health care delivery models. Thankfully, accessing health care remotely during the ongoing pandemic has become the norm. Subsequent changes to the MBS to permanently include telehealth items for GP consultations is a positive gain but one key question remains: Can the health care system integrate this model of delivery into ‘business as usual’ to ensure that virtual services to rural Australia are sustained after the pandemic?COVID‐19 has presented an opportunity to retain the gains and embed virtual health solutions as a standard mode of care. Linking‐in virtually to GPs, allied health professionals and medical specialists will offer fast and reliable access to clinical care for people living in the vast, marginalised and underserviced regions outside of metropolitan areas. Enhancing telehealth options for rural and remote Australians can also reduce the travel burden and address place, proximity and mobility challenges for vulnerable patients. There is an opportunity to craft creative telehealth models of care that can complement the skills of understaffed rural clinics and/or better facilitate telehealth partnerships between urban‐based health providers and rural patients. Firmly establishing universal telehealth as a regular and fully funded feature of rural, regional and remote health services is an unexpected, post‐pandemic benefit for rural Australians. An inclusive telehealth policy that is agnostic towards location might also go some way to reducing the high level of urban paternalism that has previously dominated the Australian health system. Therefore, while confidence in virtual models of care is high, it is time for policy‐makers and practitioners alike to make significant reductions in rural health inequity by embedding telehealth for all rural Australians as a permanent fixture in primary health care delivery models.LAC: conceptualization; data curation; formal analysis; investigation; writing – original draft. OTM: conceptualization; supervision; writing – review and editing. AWT‐R: conceptualization; supervision; writing – review and editing.Dr Lisa A. Caffery is deputy chair of the Central Queensland Hospital and Health Service Board. A/Prof Olav T. Muurlink and Prof Andrew W. Taylor‐Robinson have no conflicts of interest or relevant disclosures.No ethics approval statement as this is a commentary. Other aspects of this study that involved primary data collection were subject to CQUniversity Human Research Ethics approval (21425).


The licensed dose for omalizumab within Europe for chronic spontaneous urticaria (CSU) is 300 mg every 4 weeks, and is based on the most effective dose identified in clinical trials. However, many patients require longer‐term treatment with omalizumab and there is limited guidance on how to manage these patients. We report on a large cohort of 357 patients with CSU who have been treated over a 10‐year period on a personalized dosing regimen. Our results showed a 4% reduction in drug cost for this personalized dosing regimen compared with having all patients on the standard regimen of omalizumab 300 mg every 4 weeks. In addition, by increasing the dose, we were able to treat 22% of patients more effectively, using the principle aim of zero CSU symptoms; prior to this regimen, these patients had been achieving only partial response. Omalizumab doses and frequency should be adjusted depending on clinical response to allow for improved benefits for both patients and healthcare systems. Omalizumab doses and frequency should be titrated to clinical response. There was a 4% reduction in drug cost for our personalized dosing regimen. Updosing allowed 22% current cohort to be treated more effectively.  This was based on the most effective dose identified in clinical trials.Within our centre, omalizumab for CSU was introduced in September 2010, prior to the licensing approval. We successfully use a system whereby patients have their doses titrated up or down based on the degree of symptom control , namely the Urticaria Control Test (UCT) and the 7‐day Urticaria Activity Score (UAS7). Other PROs may be considered on an individual patient basis. The UCT provides insight into the overall level of CSU control and can be completed within an outpatient appointment. The UAS7 provides more detailed information and more importantly, variance over a longer period, e.g. the UCT may indicate poor control but review of the UAS7 may show that the patient is asymptomatic for the first 3 weeks before having their symptoms return in Week 4. Using both PROs provides a better overall picture of the patient's response to omalizumab and helps to guide treatment decisions.In complete responders, there is a patient/clinician decision at 6 months as to whether to have a treatment break or gradually extend the interval between omalizumab doses. For some patients, especially those with significant anxiety about stopping treatment or those who have had a difficult journey to complete remission, the latter is often more psychologically acceptable. At any point during the interval extension, patients can revert to the most recent effective dose if there is an increase in symptoms, with regular review and a new plan made to try extending the interval again after a mutually agreed time frame. In some patients, we have tried reductions to 150 mg per dose but this can be difficult to manage if symptoms return before the 4‐week interval, and so is not routinely included in our pathway.Dose increases (450/600 mg) for partial response are discussed by the team, revisiting symptoms to ensure no alternative diagnoses have been missed and considering alternative treatments. In some patients the effects of omalizumab diminish before 4 weeks, and in these patients reducing the interval between doses to the time at which symptoms return can be highly effective.n = 7) had moved between both lower and higher doses during their treatment pathway. Fluctuations in dose, even within the same individual, support the natural fluctuation of CSU itself. Although some omalizumab dose predictors , the evidence is limited.In our review we found that a small number of patients (2LEN/EuroGuiDerm/APAAACI urticaria guidelines on stepping down treatment, and is similar to the principles used for biologics for other conditions.For patients who need to continue treatment longer term, the overall aim is to maintain them on the lowest effective dose with regular dose reduction reviews, especially if UAS7 score is 10 and/or UCT is 16. This supports the recommendation of the EAACI/GATo conclude, our large cohort indicates that personalized dosing of omalizumab in patients with CSU is a more cost‐effective pathway, which results in more patients achieving improved response.•Omalizumab doses and frequency should be adjusted depending on clinical response.•There was a 4% reduction in drug cost for our personalized dosing regimen compared with a standard regimen.•Increasing the dose allowed 22% of the current cohort to be treated more effectively.SD and SS have received speaker fees from Novartis; the fees to SD were paid into the departmental education and training account.None.Ethics approval not applicable. The patient provided informed consent for publication of their case details and images.


The behaviour of mares is often detrimental to their performance resulting in frequent demand for methods to suppress gonadal function. In addition, prevention of unintended reproduction especially in feral horse populations may require methods for suppression of gonadal function. Surgical ovariectomy is a safe method but not an acceptable approach in feral mares and undesired in mares where future breeding is considered. There are different approaches for artificial prolongation of the luteal phase resulting in transient inhibition of oestrus and ovulation. Among those, treatment with natural or synthetic progestogens is considered the most common and successful method. Whereas application of intrauterine devices may result in prolongation of luteal function in non‐pregnant mares, intrauterine insertion of glass balls is no longer recommended because of complications in individual mares. There are several safer alternatives that may be of interest, especially for population control in free‐roaming horses. Treatment with long‐acting deslorelin implants inhibited ovulation and oestrus behaviour in mares for limited and variable time intervals in a dose‐dependent manner. The effect of GnRH vaccines varies considerably among individual mares, is age dependent, and oestrus‐like behaviour may still occur. Contraception via immunization against native porcine or recombinant zona pellucida antigen is successful, but immunocontraception is as much a result of ovarian inactivity as an antibody‐based block to sperm‐oocyte binding. In conclusion, several treatments for suppression of gonadal function in mares are available, but there are advantages and disadvantages associated that have to be considered. The treatment of choice will thus differ with regard to the demands. There are several advantages such as ease of use, biocompatibility and safety. In the horse, the effectiveness of GnRH receptor down‐regulation was previously questioned. Because of irregularities in the oestrous cycle of mares previously treated with 2.1 mg deslorelin implants for ovulation induction, the effectiveness of these implants to down‐regulate GnRH receptors was eventually proven  is a major limiting factor  antigen has been applied to various species including horses (Kirkpatrick et al., 4Although several treatments for suppression of gonadal function in mares are available, they differ with regard to their reliability, effectiveness, practicability, safety for humans and animals as well as ethical aspects. Advantages and disadvantages thus have to be considered and the treatment of choice will differ with regard to the demands. Suppression of oestrus in an individual sport horse mare or in a population of feral mares will require different approaches and pose different problems. The use of vaccines for contraception in feral horses has several limitations because treated horses require individual identification and retrieval to allow for maintenance of the vaccination schedule, long‐acting formulations must be hand‐injected, and learned aversion in treated horses may challenge repeat treatments (Joonè et al., Both authors contributed equally to the manuscript.The authors declare that they have no competing interests.


Lutra lutra) in Italy, first detected in 2003 after a southward range contraction. We modeled the rate of range expansion and occupancy at the northern expanding front , to gain insights into the progress of recovery and mechanisms of reexpansion. We performed a field survey in 2021, which redefined the northern limit of distribution further north, in close proximity to the Gran Sasso National Park. Then we analyzed a time series (1985–2021) of distances of northernmost occurrences from the center of the 1985 range. Using segmented regression, we were able to identify a prolonged stasis of the northern range edge and a simultaneous increase in occupancy from 0.151 to 0.4. A breakpoint was estimated in 2006, after which the range expanded northwards at an average rate of 5.48 km/year. From 2006 to 2021, the overall northward shift was about 80 km. Occupancy continued to increase until 2019 and abruptly declined in 2021. These patterns suggest that the reexpansion of the range can be limited by low occupancy at the expanding front. As occupancy increases, long‐distance dispersal increases and then range expands. The low occupancy at the current distribution limit of otters may reflect a higher anthropogenic pressure on northern habitats, which could slow down the reexpansion process.Species range shifts and expansion are subjects of primary research interest in the context of climate warming and biological invasions. Few studies have focused on reexpansion of species that suffered severe declines. Here, we focused on population recovery of Eurasian otters ( Lutra lutra) in Italy. We modeled the rate of range expansion at the northern expanding front  to gain insights into mechanisms of species reexpansion. We analyzed a time series of occupancy rates and distance measures on northernmost occurrences of the species (1985–2021). On the premise that the reexpansion of a species is a non‐linear process, we were able to identify the onset of reexpansion and test for different model forms underlying different hypotheses using segmented regression. The main results support the hypothesis that range reexpansion starts when the occupancy rate at the expanding front reaches a threshold value.The paper focuses on range reexpansion of the endangered Eurasian otter ( Thus, comparing contemporary and historical surveys is often the only way to documenting range changes, especially in native species. This may come at the cost of using past data collected using non‐standardized methods, often in the form of presence‐only data and with low or incomplete sampling effort  across North Pacific following translocations  in Italy at the northern range‐edge, over a period from 1985 to 2021. The Eurasian otter is a solitary, nocturnal mesocarnivore, living mainly in rivers and feeding on fishes and anurans  in the central and northern portion of the Abruzzo Region  in 2019  to the year of survey , using the AICcmodavg package . Akaike weights represent the weight of evidence in favor of model i being the best model of the suite of candidate models. We calculated the difference in AICc values of alternative models relative to the model with the lowest AICc (ΔAICc) to assess the relative level of support. Models with ΔAICc ≤ 2 have substantial support, whereas models where ΔAICc is greater have progressively less support.Statistical analyses were performed in R 4.1.2  of the northernmost occurrences. These operations produced 126 presence‐absence sites from range of periphery areas over years 1985–2021. We evaluated the relationship of occupancy probability with time by fitting segmented, quadratic, and linear models, using the same statistical methods as those for the distance‐based analysis of range expansion.Tracking species distributional edges using only distance metrics may provide incomplete inference into the range expansion. We expected that an increase in local occupancy at the expansion front would precede the onset of range reexpansion, as an effect of low long‐distance dispersal at low density. We predicted a delay in the northward expansion of the otter range in terms of an early increase in occupancy probability coupled with no significant changes in the range edge location. We were also interested in testing an occupancy decline in recent times as otters reexpand northwards along a putative increasing gradient of anthropogenic impact. This pattern may arise when small sinks populations Pulliam,  are main33.1We surveyed 77 sites along 30 watercourses of seven river basins and found evidence of otters in 11 sites Table  and know3.2wi = 0.587), it was only <2 AICc units higher than the left‐horizontal model, indicating that these two models were equally plausible (Table p < .001). From that year, the distance from the reference point increased linearly with time at an average rate of 5.48 km/year . Thus, the northern range margin did not change between 1985 and 2006 and subsequently shifted northwards  than the quadratic model (wi = 0.169), which ranked second (ΔAICc = 2.9). The remaining models received virtually no support. According to the model selected, a significant breakpoint  in occupancy probability occurred around 2019, indicating an abrupt transition from an increasing trend to a steeper decreasing one . Moreover, main watercourses are disturbed by dams and water diversion for energy production. In particular, the Vomano river and its tributaries are severely impacted by five large dams ; formal analysis ; investigation ; methodology ; writing – original draft (lead); writing – review and editing . Federico Striglioni: Conceptualization (supporting); writing – review and editing . Romina Fusillo: Conceptualization ; formal analysis ; investigation ; methodology ; writing – review and editing .Authors declare no conflicts of interest.


Sampling the insulo‐opercular region with invasive recordings is crucial given the importance of this region in epileptic networks and a variety of electroclinical presentations. However, implantation of the insulo‐opercular region via stereoelectroencephalography (sEEG) is considered technically challenging given complex vascular and gray matter relationships in this region. We investigated the safety of insulo‐opercular sEEG exploration in children and young adults using standard sEEG approaches: (1) orthogonal insulo‐opercular  and (2) medial‐lateral insular oblique approach.We performed a retrospective cohort study of 30 consecutive patients who underwent 33 sEEG implantations. All patients had drug‐resistant focal epilepsy, were between the ages of 4 and 21, and were operated at one institution between January 2019 and March 2021. Medical records and neuroimaging were reviewed. Hemorrhage, infection, and other complications were considered as outcome variables.A total of 519 electrodes were placed. Eighty‐one were placed orthogonally into the temporal operculum, 53 orthogonally into the frontal operculum, and 19 obliquely into the insula. sEEG electrodes localized seizure onset to the insulo‐opercular region in eight patients, leading to a resection three times, an ablation four times, and one peri‐insular hemispherectomy. Of the 519 electrodes placed, none of them exhibited hemorrhage or serious complications. Of the 153 electrodes placed into the insula, none had any permanent deficits or complications and one had minor bleeding due to the electrode breaking.These results demonstrate that the orthogonal  and medial approaches to sampling the insula are safe. Implanting orthogonal and medial‐lateral oblique sEEG electrodes resulted in no permanent complications in pediatric epilepsy patients.sEEG is a useful monitoring tool that often affects surgical decision making.Future work is necessary to determine seizure freedom in various invasive monitoring methods.1Identification of the epileptogenic zone (EZ) is key to planning safe and effective resective epilepsy surgery. In 30%–50% of patients, however, non‐invasive measures fail to delineate the EZ.Sampling the insulo‐opercular (IO) region with invasive recordings is crucial given the connectivity of this region to multiple brain regions in a variety of electroclinical presentations,However, the ideal approach for implantation of the IO region is still a matter of debate.Instrumentation of the IO region with electrodes can be technically challenging given the folds of the sylvian fissure, the complex orientation of cortical gray matter, and the venous and arterial structures passing through this region.This study investigates the safety of insulo‐opercular sEEG exploration in children and young adults using the (1) orthogonal  insulo‐opercular approach and (2) medial‐lateral insular approach.2We performed a retrospective review of medical records using an IRB‐approved protocol. Given the retrospective and minimal risk nature of the study, consent requirements were waived. All implantations were performed by a single surgeon. Our sEEG implantation technique is similar to that previously described.2.1We included 30 patients with 33 SEEG implantations from drug‐resistant focal epilepsy patients ages of 4 and 21 that were operated at a single institution between January 2019 and March 2021.2.2To prepare for surgery, any patients on anticoagulants or antiplatelet agents are discontinued and epilepsy medications are replaced with appropriate medication. Medications are tapered appropriately in the weeks leading up to surgery to induce and record spontaneous seizures. All patients then undergo a preimplantation neuroimaging protocol that includes (1) high‐resolution postcontrast MRI (magnetization‐prepared rapid acquisition gradient echo [MPRAGE] sequence) and (2) thin‐slice postcontrast Robotic Stereotactic Assistance (ROSA)–protocol CT.The sEEG implantation strategy is designed with the anatomo‐electro‐clinical hypothesis, which is formulated based on clinical semiology, neuropsychology, MRI findings, and long‐term video EEG recordings in mind.Patients are brought to the OR and undergo general anesthesia. A stereotactic frame with 4 head fixation points (Leksell frame) is used to position the head and ensure accuracy of stereotactic implantation. Then, bone fiducials are inserted using a 3D rendering from the ROSA software to avoid overlap with electrode trajectories and used as fiducial markers. Next, an intraoperative CT  is obtained and coregistered to the preoperative stereotactic CT by using the ROSA software. An error measurement <0.8 mm is considered acceptable. The bone fiducials are maintained in position after electrode implantation in case the patient is taken back to the OR for further electrode implantation.The robotic implantation is initialized, and the first trajectory is selected. Figure  Through An intraoperative O‐Arm CT is obtained to confirm electrode positions. This is then co‐registered to the preoperative CT using the ROSA software. The electrode positions are adjusted as necessary after comparison to preplanned positions on the preoperative MRI and adequate coverage of gray matter is assured.SEEG recordings begin a few hours after implantation. The children are monitored carefully, and antiepileptic drugs are carefully tapered to induce seizures. The electrodes are then removed under general anesthesia after the EZ is successfully localized.33.1A summary of patient characteristics and total electrodes placed is given in Table Since January 2019, a total of 519 electrodes have been placed. Eighty‐one were placed orthogonally into the temporal operculum, 53 were placed orthogonally into the frontal operculum, and 19 were placed obliquely into the insula. Among the 30 pediatric patients, the age of onset had a range from 0 to 14 years with a mean of 6.23 years and standard deviation of 4.62. The range of ages at implantation are 4‐21 with a mean of 13.42 and standard deviation of 4.53.3.2Figure More interestingly for us, sEEG changed the hypothesis from or to the IO region 9 of the 22 total times the hypothesis changed and was able to localize seizure onset to the insulo‐opercular region eight times Figure .3.3Overall, 20 patients have follow‐up seizure outcome data for at least 1 year and eight are still seizure free. Of the remaining 10 patients, three were seizure free at the latest time point which was anywhere from 0.17 to 0.92 years after surgery.3.4Table In terms of permanent neurological deficits, none of the patients developed any weakness, paresis, or other deficits that did not exist before the implantation and explantation. There were patients that had transient headaches that typically resolved after several days.4The insulo‐opercular region plays an important role in epileptic networks and there continues to be debate about the optimal methods for invasive monitoring in this region. In MR negative epilepsies in particular, localizing the EZ to the IO region can be considerably difficult.Several other techniques have been described for invasive monitoring of the IO region. Open, image‐guided, depth electrode techniques are described, which can be employed as part of a craniotomy and grid electrode implantation.There are advantages and disadvantages of the orthogonal and oblique approaches to the IO region. The orthogonal approach enables simultaneous sampling of both the operculum and insula through a single short trajectory. One disadvantage of this approach is that the M2 branches of the MCA can make it difficult to access the inferior aspect of the first insular gyrus, which can necessitate use of an oblique trajectory. Another disadvantage of the orthogonal approach is that the position of insular recordings can depend on the orientation of MCA branches on preoperative vascular imaging. Although some surgeons always implant using a completely orthogonal approach to the insula with the assumption that electrodes will be deflected by arteries in their path, our practice is to place electrodes pseudo‐orthogonal (terminating outside the circular sulcus recording from the insulo‐opercular transition) when cerebrovasculature is not favorable for a direct orthogonal approach. The medial‐lateral oblique approach provides dense coverage of the insular gray matter but does not simultaneously record from the operculum. Given the length of insular oblique trajectories and the importance of distal electrode contacts, these trajectories are probably more prone to inaccuracies, although we did not see any instances of this in our series. Furthermore, it is important to note that with the standard orthogonal approach often only 1‐2 electrodes terminate in the insular gray matter, which is much fewer than the oblique approach.Although our study focuses on the safety of insular‐opercular sEEG approaches, it is crucial to note that our findings also reveal that recordings from these electrodes are often relevant (see Figure A limitation of the existing literature is that most studies have been done in adult populations and although sEEG has also been shown to be effective in pediatric populations in Europe, very few studies have been done in the USA.Several limitations of the present study should be suggested. While these data show the safety of orthogonal and medial‐lateral oblique sEEG approaches to the IO region, the optimal approach between these two techniques is not resolved by our data. Further, lack of a direct comparison between sEEG approaches to the IO region and other approaches leaves optimal invasive monitoring modality an open question. With those limitations in mind, our results do show that sEEG approaches to the IO region can be safe and that open approaches are not necessary for invasive monitoring of this region.It is also important to note that sEEG complication rates probably differ from center to center based on variation in technique. Some centers have reported up to 19% sEEG hemorrhage rates5Insulo‐opercular sEEG via orthogonal and medial‐lateral oblique is safe in pediatric epilepsy surgery patients. Our results also show that IO sEEG frequently influences pediatric epilepsy surgery resection plans. Future work may help to understand the relative risk‐benefit profile of different IO invasive monitoring approaches.All authors contributed to the collection and analysis of data.Dr. Abel is a consultant for and receives research funding from the Monteris Corporation.An IRB‐approved protocol was used and given the retrospective and minimal risk nature of the study, consent requirements were waived.


Cetaceans are important consumers in marine ecosystems, but few studies have quantified their climate responses. The rapid, directional warming occurring in the Northeast United States (NEUS) provides a unique opportunity to assess climate impacts on cetaceans. We used stranding data to examine changes to the distribution and relative abundance of odontocetes from 1996 to 2020 in both the NEUS and the Southeast United States (SEUS), which is not warming. We conducted simulations to determine the number of stranding events needed to detect a distributional shift for each species given the speed of the shift and the spatial variability in strandings. We compared observed shifts to climate velocity. Smaller sample sizes were needed to detect more rapid poleward shifts, particularly for species with low spatial variability. Poleward shifts were observed in all species with sufficient sample sizes, and shifts were faster than predicted by climate velocity. For species whose trailing edge of distribution occurred in the NEUS, the center of distribution approached the northern limit of the NEUS and relative abundance declined through time, suggesting shifts north out of US waters. The relative abundance of warm water species in the stranding record increased significantly in the NEUS while that of cool water species declined significantly as their distributions shifted north out of the NEUS. Changes in the odontocete community were less apparent in the SEUS, highlighting the importance of regional warming. Observed poleward shifts and changes in species composition suggest a reorganization of the odontocete community in the NEUS in response to rapid warming. We suggest that strandings provide a key dataset for understanding climate impacts on cetaceans given limitations of survey effort and modeling approaches for predicting distributions under rapidly changing conditions. Our findings portend marked changes to the distribution of highly mobile consumer species across international boundaries under continued warming. Odontocetes are important consumers in marine ecosystems, but few studies have quantified their climate responses. Waters of the Northeast United States (NEUS) are undergoing rapid, directional warming. Using stranding data, we observed poleward shifts in the distribution of strandings for all odontocete species with sufficient data. We found that the relative abundance of warm water odontocete species in the stranding record increased significantly in the NEUS while that of cool water species declined significantly as their distributions shifted north out of US waters. Our results suggest a reorganization of the odontocete community in the NEUS in response to rapid warming. Continuous poleward distributional shifts and rates of such shifts in the distribution of other odontocete species have not been quantified to date or linked with the pace of climate‐driven oceanographic change. In addition, the rapid warming occurring in the NEUS is not observed in the Southeast United States (SEUS), where temperature trends are not significant or weakly cooling . Level A data include information such as the species identification, location, and condition of the stranded animal. In the SEUS, stranding data were curated by NMFS as part of the Marine Mammal Health and Stranding Response Program (MMHSRP) National Database from 1996 onward  from 1996 to 2020 that were used in subsequent analyses (sample size by species is shown in Table 2.2We used the framework of MacLeod  to groupPhocoena phocoena), long‐finned pilot whales and Atlantic white‐sided dolphins (Lagenorhynchus acutus) showed trailing edge distributions in this region. For these species, we assessed shifts in both the center and trailing edges of their distributions. No species that were well represented in the stranding data showed leading edge distributions in the study area.We used the locations of species sightings from stock assessment reports  to spatial temporal gradients (°C km−1) is calculated to develop an index of climate velocity in km year−1 (°C year−1/°C km−1 = km year−1). We used the VoCC packages described in Burrows et al. (−1) in a 3 × 3 cell neighborhood. The temporal gradient was calculated as the slope of the linear model of changes to SST through time (°C year−1).We used annual mean NOAA OI sea surface temperature (SST) data with a spatial resolution of 0.25° from 1996 to 2020, provided by the NOAA/OAR/ESRL PSL, Boulder, Colorado, USA: S Figure  and to cS Figure  to assess et al.  to calcu2.4Following preliminary analyses indicating linear relationships between variables, we used linear regressions to assess changes in SST anomaly in the NEUS and SEUS, respectively, as well as changes in species composition and shifts in species distributions through time. We examined changes in the relative abundance of stranding for individual species, and species in each of the four climatic categories , and modeled these changes relative to annual SST anomaly using linear regressions. The Dunn–Šidák method was used to constrain the Type I error rate across multiple comparisons Kirk, .Tursiops truncatus), common dolphins (Delphinus delphis), Atlantic white‐sided dolphins, striped dolphins , Risso's dolphins (Grampus griseus), long‐finned pilot whales, pygmy sperm whales (Kogia breviceps), and dwarf sperm whales (K. sima). Range maps for these species are shown in Figure −1. For the six species for which simulation analyses indicated sufficient data for further analyses , we compared observed shifts in the distribution of strandings and examined changes in the proportion of strandings for that species by year. We used nonparametric bootstrap sampling methods to estimate 95% confidence intervals , we assessed poleward shifts in distributions. The following nine species met this criteria: harbor porpoise, bottlenose dolphins . To examine the relationship between these factors and to determine the minimum mean sample size of stranding events needed to observe a trend, we simulated poleward distances for stranding events in each year with a simple linear model and varied sample size, variance in poleward distance, and slope. Details of the modeling methods are described in the Supplementary Information.2.6www.census.gov). Census data are available at 10‐year intervals, and thus we assessed changes in population between 2000 and 2020 to best match the timeframe for which strandings were assessed (1996–2020). Census data provided population counts for 2000 and demographic analysis estimates for 2020.Human observers must be present to record marine mammal strandings along the coastline, and changes in observer coverage or human population can influence the number of strandings reported  to determine whether there were any spatial patterns of population growth that might impact our results . Specifically, we assessed whether human population change was related to poleward distance at the centroid of each coastal county using linear regressions. Regressions were performed both for the east coast as a whole, and for any species showing a poleward shift in the distribution of strandings, within the poleward distances over which the shift was observed. The Dunn–Šidák method was used to adjust α for multiple comparisons Kirk, .All analyses were conducted using R Statistical Software . Conversely, the highest temporal gradients in SST were observed in the northern NEUS . Climate velocity was significantly higher in the NEUS than the SEUS during this period, with median values of 4.41 and −0.22 km year−1, respectively  for Atlantic white‐sided dolphins and 40.6 km year−1 (95% CI 16.0–54.1 km year−1) for long‐finned pilot whales, respectively  were insufficient to model poleward shifts Table . We obsely Table . Two of ly Table ; Table 1ly Table . Slopes −1 Table . All obs−1, 4 and 6 strandings per year, respectively, were required to detect a significant poleward shift in the center of distribution for Atlantic white‐sided dolphins and common dolphins. Species with low mean annual variance in poleward distance such as Atlantic white‐sided dolphins, long‐finned pilot whales and common dolphins (Table −1). In contrast, approximately 77–154 strandings or more would be required to detect poleward shifts at this slope for Risso's dolphins and pygmy sperm whales. The results of the simulations suggested that for striped dolphins, Risso's dolphins, and pygmy sperm whales, there were fewer stranding events observed than the number required to detect a significant shift 95% of the time unless slopes were greater than approximately 20, 26 and 40 km year−1, respectively  necessary to detect a significant poleward shift for a given slope varied considerably between species. Smaller sample sizes were needed to detect poleward shifts with higher slopes Figure ; Table 3Census data indicated that most counties along the eastern seaboard of the United States demonstrated population increases from 2000 to 2020 (77.7%). The counties with the largest population increases generally occurred in the SEUS Figure . Distanc4The stranding dataset along the long coastline of the eastern seaboard of the United States, covering approximately 20° of latitude, provides a compelling scenario for examining changes to odontocete distributions in relation to climate‐driven oceanographic change. Waters of the NEUS have warmed dramatically in recent years, allowing stranding data to be assessed relative to rapid, directional climate change. Our results demonstrate marked shifts in the spatial distribution of strandings of cool water odontocete species linked with rapidly warming waters in the NEUS, and suggest that the distribution of these species is shifting north, out of the NEUS. Observed poleward shifts from 1996 to 2020 indicate that the center of distribution for strandings of cool water odontocete species was at or approaching the northern extent of the NEUS at the end of this study period. Furthermore, our observation that the center and trailing edge of the distribution of strandings for long‐finned pilot whales and Atlantic white‐sided dolphins converged in recent years suggests that the center of distribution may underestimate recent shifts in distribution out of US waters. The center of distribution was calculated using only data from the NEUS given the availability of consistently recorded data, and likely did not reflect the true center of distribution as the species shifted north out of the NEUS. The proportion of cool water odontocete species declined through time and was strongly linked with SST anomaly in the NEUS, providing further support for poleward shifts out of this region in association with rapid warming. Species‐level assessments suggested that declines in strandings of cool water species were driven by declines in the relative abundance of harbor porpoise, long‐finned pilot whale, and to a lesser extent Atlantic white‐sided dolphin strandings. Increases in warm water species were driven by common dolphin strandings in the NEUS, as well as bottlenose dolphins. The relative abundance of strandings for a particular species could be influenced by changes to the population size of those species, but due to insufficient data and changes in methodology, trends in abundance for our focal species cannot be determined  and exceeded climate velocity typically observed in the NEUS , indicating that shifts were occurring faster than would be expected based on temperature. Recent studies suggest that most range shifts in marine species track changes in temperature , or 40 km year−1 (Risso's dolphins) occurred. Thus, it is not possible to determine whether these species are not shifting in response to warming waters or whether they are shifting at more moderate rates that could not be detected with the available data.Assessing distributional shifts is key to understanding the biological impacts of climate‐driven warming, but sample sizes may limit the ability to detect and quantify shifts. In the present study, simulation analyses provided a useful means of assessing the statistical power of observed poleward shifts in the distribution of odontocete strandings. Our results highlighted that for some odontocete species, poleward distributional shifts can be assessed using a relatively small number of strandings depending on the speed of the shift and the spatial variability of the species' distribution. Simulations suggested that given the observed sample sizes for three of the focal warm water species , poleward shifts would not have been detectable unless rapid shifts of approximately 22 km yearOur findings highlight the utility of stranding records for assessing broad changes in the distribution of cetacean species and species composition of cetacean communities. Cetacean distribution is typically assessed using data from at‐sea surveys, which are both expensive and labor intensive. Because cetacean species occur at low densities and have wide distributions, effort for standardized at‐sea surveys is often too low and does not cover sufficient spatiotemporal scales to allow changes to the abundance or distribution of cetacean populations to be detected (Jewell et al., We assessed whether changes to the human population along the eastern seaboard of the United States might have contributed to observed patterns of strandings, and we did not find evidence suggesting that this was the case. However, studies assessing trends in the distribution of strandings should consider patterns of human use of coastal regions, particularly for more fine‐scale analyses. The widespread use of technological devices such as smartphones and georeferenced cameras has produced huge quantities of data that can be used to assess patterns of human movement and behavior (de Arriba‐Pérez et al., Our approach focuses on broad, long‐term trends in odontocete distribution and species composition to understand the impacts of warming waters in the NEUS on cetaceans. Lower frequency environmental effects are also important to understanding environmental drivers of cetacean distribution, and stranding data may also be useful in assessing smaller‐scale patterns. For example, the proportion of cool water odontocete species occurring in the NEUS suggested a periodic increase in these species occurring every 3–6 years Figure  and may 5Together, our findings suggest widespread impacts of rapid warming on the distribution and species composition of odontocetes in the NEUS. Changes in the relative abundance of strandings suggest that warm water species have become more abundant in the NEUS as cool water species have shifted north out of the NEUS and have become less abundant. Changes to the cetacean community were less apparent in the SEUS, highlighting the importance of regional warming in driving changes to the cetacean community along the eastern seaboard of the United States. Simulations provided helpful context for understanding data required to demonstrate poleward shifts in distributions under climate change. Our results demonstrate the utility of the stranding record for understanding climate impacts on the relative abundance and community structure of cetaceans given limitations of at‐sea survey effort and modeling approaches for predicting distributions under rapidly changing conditions.The authors declare no conflict of interest.Appendix S1Click here for additional data file.


Patterns of biodiversity provide insights into the processes that shape biological communities around the world. Variation in species diversity along biogeographical or ecological gradients, such as latitude or precipitation, can be attributed to variation in different components of biodiversity: changes in the total abundance  and changes in the regional species abundance distribution (SAD). Rarefaction curves can provide a tool to partition these sources of variation on diversity, but first must be converted to a common unit of measurement. Here, we partition species diversity gradients into components of the SAD and abundance using the effective number of species (ENS) transformation of the individual‐based rarefaction curve. Because the ENS curve is unconstrained by sample size, it can act as a standardized unit of measurement when comparing effect sizes among different components of biodiversity change. We illustrate the utility of the approach using two data sets spanning latitudinal diversity gradients in trees and marine reef fish and find contrasting results. Whereas the diversity gradient of fish was mostly associated with variation in abundance (86%), the tree diversity gradient was mostly associated with variation in the SAD (59%). These results suggest that local fish diversity may be limited by energy through the more‐individuals effect, while species pool effects are the larger determinant of tree diversity. We suggest that the framework of the ENS‐curve has the potential to quantify the underlying factors influencing most aspects of diversity change. Here, we partition diversity gradients into components of the SAD and abundance using the effective number of species (ENS) transformation of the individual‐based rarefaction curve. Comparing well‐known latitudinal gradients of trees and reef fish, we find that although both groups show similar richness gradients, they differ substantially in the contributions of the more‐individuals effects . Our approach opens new doors for the synthesis of biodiversity trends due to natural and anthropogenic changes. DiversiN] supported by the environment), and (3) the spatial distribution of species in the region (e.g. intraspecific aggregation and interspecific associations). The interplay of these mutually dependent components determines the shape of the regional species–area relationship and ultimately the diversity of local samples at any spatial scale , it is generally advised to consider several metrics of biodiversity simultaneously because different incidence and abundance‐based diversity metrics  capture the aspects of multidimensional diversity change in a complementary manner  and associated passive sampling effects. The SAD‐component can be thought of as the sample's expected diversity for a standard number of individuals (n), and the N‐component is the portion of the observed diversity that is attributable to the fact that a sample exceeds this standard number of individuals . Then, we can analyze and compare the changes in the two components , rather than simply analyzing the total diversity change. To calculate the components, we use the effective numbers of species (ENS) transformation of the rarefaction curve  and show that they emerge from different relative contributions of changes in the regional SAD and in the number of individuals.Here, we present a quantitative dissection of the relative importance of changes in 2Our approach relies on a family of diversity measures that was first introduced as “Hurlbert ENS” by Dauby and Hardy . Here, wRelating the complementary information given by a set of diversity measures to the diversity components discussed above is challenging because many metrics are sensitive to more than one component , where the diversity order, q, tunes the weight of species abundances pi  is constant along a gradient of interest while 0D  increases, this pattern can be underlain by a change in the regional SAD , a passive sampling effect  or both.The Hill number framework solves the problem of incompatible numerical constraints by converting diversity index values to effective numbers of species  and expected species richness  is the IBR curve  are not directly comparable to those at higher values of n . Again, ENS refers to the number of species in a hypothetical, perfectly even community that has the same rarefied richness as the real community  is also the ENS transformation of Hurlbert's . Increases along the ENS curve are entirely due to the incremental influence of rare species and do not result from variable numerical constraints along the curve. Therefore, the ENS transformation makes it easy to assess relative evenness; random samples from perfectly even communities  produce ENS curves that are flat horizontal lines ; second, a change in the regional SAD ; and third, a combination of more‐individuals effect and SAD change . The first row of Figure Figure n = 1000). Beyond that, the tropical community passively samples additional rare species due its larger sample size (labeled as “N‐effect”). In the SAD change scenario (panel e), the ENS transformation reveals that the tropical community has a higher number of relatively dominant species to start with (i.e. E2), and then accumulates relatively rare species at a higher rate than the temperate community, adding up to the total SADeffect (labeled “SAD‐effect”). The same SAD‐effect can be observed in the combined scenario (panel f), but now the tropical community also has additional rare species due to its higher number of individuals (labeled “N‐effect”). As along the ENS curve all values are expressed in terms of effective numbers of species, we can directly compare the magnitudes of the two effects. In this example (panel f), most of the observed diversity change is attributed to changes in the regional SAD (ca. 80%), while the contributions of the more‐individual effect are relatively small (ca. 20%).While the IBR curves allow us to qualitatively and visually distinguish the scenarios, they do not directly enable a quantitative decomposition of the observed diversity change into contributions of more‐individuals effects and SAD. Therefore, we apply the ENS transformation to free IBR curves of their numerical constraints. The resulting ENS curves (second row) are similar to the IBR curves in that changes in their shape reflect changes in the SAD, but the start of the curve is no longer constrained. In the more‐individuals scenario (panel d), both communities have the same diversity for any common number of individuals (up to EN) into two components: The SAD‐component is simply the ENS for a standard number of individuals (i.e. En), where n is typically the sample size of the smallest community in the gradient. Then, the N‐component is the difference between the total diversity and the SAD‐component (i.e. EN – En). It reflects the more‐individuals effect with respect to n individuals (i.e. how much more diversity does a community have because its sample size exceeds n). Now, instead of considering the total diversity (EN), we can analyze these components along the gradient of interest. This is shown in the last row of Figure N‐components of the two example communities. Note that adding up the two components yields the total diversity of the communities. In the first scenario, the diversity change occurs exclusively in the N‐component , while in the second scenario, the diversity change is driven by the SAD‐component . Finally, in the third scenario both components change at the same time, so that N effect and SAD effect add up to the total diversity gradient. By comparing the slopes of the two components along the gradient (dashed lines), we can assess the relative contributions of N effects and SAD effects to the observed diversity gradient. The pie charts in Figure N effects for each scenario. In the combined scenario (panel i), the SAD effect contributes 80% toward the total diversity gradient while 20% of the diversity change occurs because the tropical community has more than 1000 individuals. In practice, these effect sizes correspond to the regression coefficients of linear models. However, the components could also be modeled as non‐linear functions of continuous predictors. In that case, the contributions of N and SAD effects may be variable along the gradient and cannot be summarized as a simple pie chart.To apply this approach to any number of communities, we can partition the total diversity of each community . Our simulations show that the SAD‐component responded to changes in the species pool but remained unaffected by total abundance  in reef fish and trees. The trend of increasing diversity from poles to equator is one of most prominent global biodiversity patterns that occurs in many taxa and at different spatial scales Fine, . All comN is expected to vary with energy‐ or resource availability and, accordingly, the more‐individual hypothesis (MIH) is one of the classic explanations for the LDG  forest trees from the Gentry plot dataset Gentry,  and (2) Because our main focus was to illustrate the analytical framework, rather than an exhaustive analysis of these data sets, we reduced both data sets into one latitudinal “slice” to minimize other well‐known confounds, such as biogeographic factors, that influence the magnitude of the gradient. For trees, we focused on the plots located in the Americas, so as to avoid the potential influence of continent on tree diversity  for n = 20 and derived the corresponding ENS values using Equation 3 in Table EN and En, respectively). En represents the SAD‐component. The difference between EN  and En (SAD‐component) is the diversity component that results from the changes in N or the more‐individuals effect (N‐component). We then modeled the two components along the latitudinal gradient using simple linear models with absolute latitude as the independent variable, and the SAD and N‐components as dependent variables. We used the regression coefficients (or slopes) as the effect sizes for the respective components. Since our partitioning framework is additive and models are linear, the effect sizes (i.e. slopes) of the two components add up to the effect size (i.e. slope) of the total diversity gradient.After selecting the sites, we dissected the observed diversity of each sample into the SAD‐component and the N‐effect also contributed to the total diversity gradient, as total tree abundance tended to increase as absolute latitude decreased. In contrast to the trees, the reef fish diversity gradient was strongly dominated by the N‐effect. For a standardized number of individuals, the fish diversity gradient was relatively weak (see SAD‐component). This reflects that species rich reef fish communities are often dominated by a few species, the number of which does not vary strongly along the gradient. For a constant sample size, the many rare species in diverse fish communities have little weight in the diversity estimate. That is, they mostly affect the diversity for communities with more individuals and are captured more‐individual effect.Both trees and reef fish showed similar slopes along their respective latitudinal gradient for the overall richness gradient, but they differed in how the underlying component contributions changed along the gradient Figure . The treN‐effect in fishes.The contrasting results between fishes and trees could reflect biological differences of the two groups. Fish move in a three‐dimensional space, which allows for much stronger gradients in total abundance. In forests, on the other hand, stem density is likely more strongly limited by available space. This suggests that for forests, community assembly processes change more strongly along the gradient, leading to communities with high relative evenness in the tropics . Whereas, for reef fishes the diversity gradient was mostly underlain by more‐individual effects (86%). Our case study shows that our approach has great potential for quantitative synthesis studies that analyze the heterogeneity in seemingly general diversity patterns (such as the LDG).PIE, Sn, S, N) , and that all species have the same detection probability. Whenever these assumptions are violated, sample‐based rarefaction approaches may be more appropriate ; formal analysis (lead); methodology (lead); visualization (lead); writing – original draft (lead). Shane A. Blowes: Conceptualization (supporting); formal analysis (supporting); methodology (supporting); supervision (supporting); writing – original draft (supporting); writing – review and editing . Daniel J. McGlinn: Conceptualization (supporting); methodology (supporting); writing – original draft (supporting); writing – review and editing . Nicholas J. Gotelli: Conceptualization (supporting); methodology (supporting); writing – original draft (supporting); writing – review and editing . Brian J. McGill: Conceptualization (supporting); methodology (supporting); writing – original draft (supporting); writing – review and editing . Jonathan M. Chase: Conceptualization (supporting); formal analysis (supporting); methodology (supporting); supervision (lead); writing – original draft (supporting); writing – review and editing .The authors declare that there are no conflicts of interest.Fig S1Click here for additional data file.Fig S2Click here for additional data file.Fig S3Click here for additional data file.