The conservation of long‐distance migratory birds requires coordination between the multiple countries connected by the movements of these species. The recent expansion of tracking studies is shedding new light on these movements, but much of this information is fragmented and inaccessible to conservation practitioners and policy makers. We synthesized current knowledge on the connectivity established between countries by landbirds and raptors migrating along the African–Eurasian flyway. We reviewed tracking studies to compile migration records for 1229 individual birds, from which we derived 544 migratory links, each link corresponding to a species’ connection between a breeding country in Europe and a nonbreeding country in sub‐Saharan Africa. We used these migratory links to analyze trends in knowledge over time and spatial patterns of connectivity per country (across species), per species (across countries), and at the flyway scale . The number of tracking studies available increased steadily since 2010 (particularly for landbirds), but the coverage of existing tracking data was highly incomplete. An average of 7.5% of migratory landbird species and 14.6% of raptor species were tracked per country. More data existed from central and western European countries, and it was biased toward larger bodied species. We provide species‐ and country‐level syntheses of the migratory links we identified from the reviewed studies, involving 123 populations of 43 species, migrating between 28 European and 43 African countries. Several countries  are strategic priorities for future tracking studies to complement existing data, particularly on landbirds. Despite the limitations in existing tracking data, our data and results can inform discussions under 2 key policy instruments at the flyway scale: the African–Eurasian Migratory Landbirds Action Plan and the Memorandum of Understanding on the Conservation of Migratory Birds of Prey in Africa and Eurasia. Migratory birds undertake spectacular movements across continents and oceans, coupling distant ecosystems . We compiled all available tracking data on the links between countries created by landbirds and raptors as they migrate from breeding to nonbreeding grounds. We then synthesized the current knowledge regarding these connections at the level of individual countries, individual species, and at the flyway scale. Finally, we evaluated the extent of the remaining gaps in knowledge, proposing priorities for future bird‐tracking studies that can strategically reduce those gaps.Within the African–Eurasian migratory flyway, we focused on breeding grounds in Europe (including Turkey and excluding Russia) and on nonbreeding grounds in sub‐Saharan Africa  Appendix . We did We analyzed 118 long‐distance migratory bird species (91 landbirds covered by the AEMLAP and 27 raptors covered by the Raptors MOU), all breeding in Europe and spending the nonbreeding season in sub‐Saharan Africa Appendix . We usedpopulation only to refer to a single species in a single country). We used national boundaries to define populations because our aim was to characterize links between countries. Although these national populations are not ecologically isolated, patterns of natal and breeding dispersal are likely negligible at this scale  populations, a single European population, and 1 or more European and African subpopulations.We used the terms We used the European Red List of Birds  and the one where it spends the most time during the nonbreeding season (nonbreeding country). As we extracted data from available studies rather than from raw tracking data (see below), we were unable to extract finer details  across all individuals.An individual migratory bird typically crosses the borders of multiple countries during its annual cycle, including where it breeds, stops over during migration, and spends the nonbreeding season. We focused on 2 countries per individual: the one where it breeds  migrate to the same African country, they establish a single migratory link of 100% strength. If instead the birds spread across multiple African countries, they establish multiple links of lower strength. This measure of strength is directional . Although ringing data can provide robust insights on migratory connectivity  and Google Scholar (https://scholar.google.com/), complemented by additional studies identified through extensive ad hoc searches on Google and consulting previous reviews , and the nonbreeding country  (details in Appendix Caprimulgus europaeus), Eurasian bee‐eater (Merops apiaster), barn swallow (Hirundo rustica), and collared flycatcher , the tracking data revealed nonbreeding ranges covering more countries than those identified by BirdLife International and Handbook of the Birds of the World (For European nightjar (he World . Therefohe World  & S6 befobserved links (derived from the migration records) underestimated the true number existing for each population. Nevertheless, some missing links were predictable and were inferred through interpolation between known links. For example, if for a given population breeding in European country A the migration records showed connections to 2 African countries, B and C (through observed links A–B and A–C), and if there was a third country D spatially located between B and C that was also within the species’ nonbreeding range, then link A–D likely also existed and, in such cases, we inferred that the population also migrates to country D  and excluded from further analysis any populations with fewer than 3 migration records. For each population, we then identified 1 or more migratory links (between a European and a sub‐Saharan country). Given the incompleteness of our data set, these https://african‐eurasian‐migrants.shinyapps.io/migratory_links/.Assuming tagged birds are representative of their populations, the strength of a migratory link can be estimated from the distribution of migration records among the migratory links in a population , per species (across countries), and at the flyway scale . We analyzed data for landbirds and raptors separately.We plotted the cumulative number of studies and migratory links (observed and inferred) over time, as indicators of trends in knowledge of migratory connectivity between countries along the African–Eurasian flyway. We also plotted the relationship between the number of migration records per population and the number of migratory links to investigate whether tracking effort per population appeared sufficient.For each of the analyzed countries (European or African), we synthesized connectivity with other countries by plotting all the corresponding migratory links according to strength.For each of the species in our data set, we synthesized the connectivity between breeding and nonbreeding countries by plotting all migratory links for each population and estimating how representative each link is of the species’ overall European population by weighting its strength relative to the percentage of the total European population breeding in each country. We then quantified the importance of each sub‐Saharan country as a nonbreeding destination for that particular species by summing the weighted values across all migratory links to each African country.We synthesized current knowledge of spatial patterns of connectivity between countries in the flyway by generating a map of the known migratory links across all species, a map with the number of migratory links per country, and a map of the number of tracked species per country.For each country in Europe or in sub‐Saharan Africa, we quantified the extent of knowledge gaps by calculating the percentage of long‐distance migratory species per country present in the country but for which we did not find migratory links. This value varied from 0% (no gaps) to 100% .Streptopelia turtur) breeds in western Europe and has the subregional population distributed across 7 countries: Spain (73.8%), France (24.9%), Portugal (0.9%), the United Kingdom (0.2%), Belgium (0.2%), the Netherlands (<0.1%), and Luxemburg (<0.1%). Our data set included migratory links for France and the United Kingdom , so we highlight the turtle dove in Spain as a priority for future tracking. Through this process, we obtained a set of unique species–country combinations, each highlighting a particular species that we considered a priority for tracking in a particular country, which we synthesized into a list to support future tracking initiatives in each country.We recommend that any flyway‐wide strategy for tracking long‐distance migratory birds to fill knowledge gaps should prioritize species with decreasing populations  Appendix ; priorithttps://www.naturalearthdata.com/) in the sf package  and 51 additional studies obtained through complementary searches. We retained 132 studies from which we gathered 1282 migration records  in our data set dated from 1996, and the cumulative number of studies and links increased steadily over time Figure  and to 5The number of migratory links per population tended to increase with the number of migratory records, even if there was substantial variation around this trend Figure . The incMapping migratory links per country revealed their connections to other countries through the long‐distance migrations of bird populations Figure . We founThe number of migratory links per species varied substantially and was generally higher for raptors average 16.6) than for landbirds  from the 5 populations in our data set spread across 21 African countries, which were estimated to receive from <1% (Liberia) to 9.3% (Sierra Leone) of the European population (Appendix Circus pygargus) from 7 populations in Europe concentrated in 9 African countries, which were estimated to receive from <1% (Ghana) to 23.9% (Niger) of the European population. Mapping all migratory links per species , but also Mauritania , Nigeria , and Burkina Faso . Countries in central and southern Africa also stood out for links for landbirds (but not for raptors), in particular the Democratic Republic of Congo , Angola , Botswana , and Namibia . We found few links and few tracked species for countries in eastern Africa .The vast majority of long‐distance migratory bird species in each country had not been tracked Figure . In EuroWe identified 287 species–country combinations as priorities for future tracking (6.5% of the gaps) Appendix , mostly Our study sheds light on the wealth of data acquired from the tracking of thousands of African–Eurasian migratory landbirds and raptors from 1996 to 2021 Appendix . CompilePhylloscopus trochilus) disperses across 9 countries in western and central Africa  tagged in 6 European countries established fewer but stronger links (26%) with 6 southern African countries  had contrasting patterns across populations. Finish breeding birds dispersed broadly across 11 countries in Africa  in the Balkans is now being applied to reduce these threats along the eastern flyway after tracking identified where these threats were most prominent  breeding in Spain that 66% migrates to Mauritania and 33% to Senegal and Gambia, but this was based on just 3 individuals. Furthermore, for those populations tracked with archival tags (mainly GLS [birds must be recaptured to recover the tracking data]), spatial variation in mortality during the nonbreeding season can affect the distribution and strength of migratory links.The incompleteness of and biases in our data set mean there are caveats to our interpretation of results. Estimates of relative strength of migratory links per population Appendix  need to Insufficient and biased coverage of tracked populations across Eurasia may have led to strong underestimates of the importance of parts of the nonbreeding range for many species. For example, all 25 migratory links we found for the lesser kestrel pointed to western African countries as major nonbreeding grounds Figure . HoweverOur data set is also taxonomically biased. It covered only 32% of the landbirds analyzed and 52% of raptors for which we could find tracking records. Besides the number of species, body size played a major role in this bias because devices for tracking smaller species have only been developed recently and, even today, larger devices have many advantages, such as reliability, longer battery life, and remote data transmission .Our proposed priorities are intended as an illustration of how the available data can underpin a strategic plan to guide research for filling knowledge gaps. Although we recommend the general principles proposed , stakeholders may well want or need to incorporate other factors into their decision‐making process . We believe the data we collated and synthesized, integrated with complementary ringing data  and the Seabird Tracking Database (http://seabirdtracking.org/) host billions of animal locations .Appendix S2: Species list and population trends ‐ Table S2. List of the 118 species of African–Eurasian long‐distance migratory landbirds and raptors analyzed. Common name, scientific name and synonyms as used in the literature reviews search strings (details in Appendix S3). European population trend  according the European Red List of Birds .Appendix S5: Updated no‐nbreeding range maps ‐ Figure S5. Updated nonbreeding range maps used in this study for: (a) European nightjar, (b) European beeeater, (c) barn swallow, and (d) collared flycatcher ‐ shapefiles in Appendix S6 (separate file)Appendix S7: Estimation of migratory links' strength ‐ Figure S7. Taking as example the lesser kestrel  population breeding in Greece, the figure below illustrates: (a) the observed migratory links, with the number of migration records  as obtained from the literature. The area in dark blue corresponds to the species’ nonbreeding range as mapped in BirdLife International and Handbook of the Birds of the World (2018) within the countries with migration records; in light blue the nonbreeding range elsewhere. For each migratory link, the position in the nonbreeding country is the centroid of the respective dark blue polygon. (b) Minimum convex polygon encompassing the centroids in nonbreeding countries. This touches the nonbreeding range within 2 additional countries (in violet), resulting in 2 new inferred migratory links (dashed lines). (c) Number of migratory records for the inferred migratory links (see formula in main text), estimated from the density of records in neighboring countries. (d) Estimated strength of migratory links created by a population of lesser kestrels migrating between Greece and each of 6 countries within the species’ nonbreeding range in Sub‐Saharan Africa.Appendix S8: Migration records by European region ‐ Figure S8. Number of migration records compiled in this study and respective populations organized by region in Europe.Click here for additional data file.Supporting MaterialClick here for additional data file.Appendix S9. List of migratory links; also available in a virtual application at https://african‐eurasian‐migrants.shinyapps.io/migratory_links/Click here for additional data file.Appendix S10. Mapping country‐level connectivity for all countries in Europe and sub‐Saharan Africa.Click here for additional data file.Appendix S11. Mapping species‐level connectivity for species of long‐distance migratory landbirds and raptorsClick here for additional data file.Appendix S12: List of species‐country combinations identified as priorities for future trackingClick here for additional data file.


During the COVID 19 pandemic, advanced age, scoring systems, and a shortage of ICU beds were used as cut‐offs for ICU admission. This case report describes the epicrisis of an elderly patient who was almost mistakenly not treated in an ICU. Chest radiograph of a 90‐year‐old patient with bipulmonary infiltrates typical of COVID‐19, already covering 70% of the lung parenchyma. The unexpectedly positive disease course in this 90‐year‐old patient raises ethical conflicts related to the COVID‐19 pandemic, standard triage practice at the time, and the frailty score used for this purpose. At this time, the patient had received his basic immunization with one COVID‐19 vaccine only 8 days before the onset of illness. Sequence analysis revealed the presence of variant B1.1.7. In the emergency department, he immediately received oxygen therapy with a high‐flow nasal cannula (HFNC) and immunomodulatory therapy with dexamethasone 6 mg according to the German S3 guidelines at that time. As a result of acute to chronic renal failure, an initial creatinine of 320.89 μmoL/L was detected. The patient had been suffering from persistent vomiting and diarrhea for several days and shows an additional existing hypernatremia (153 mmoL/L) and a lactate value of 1.8 mmoL/L.Ten days after a positive reverse transcriptase polymerase chain reaction (RT‐PCR) test for SARS‐CoV2, a 90‐year‐old patient was admitted to the emergency department of our tertiary university hospital by his primary care physician with a rapid deterioration of his general condition and existing hypoxemia  4, Simplified Acute Physiology II Score (SPAS‐II) 50, Therapeutic Intervention Scoring System (TISS‐28) 22, Charlson comorbidity index (CCI) 12, and Clinical Frailty Scale (CFS) 7. Due to an intrapartum rhesus incompatibility reaction, both the patient and his twin brother suffered from infantile hypoxic brain injury. During the Nazi regime in Germany, the parents succeeded only with difficulty in hiding both children from the then threatened “euthanasia” by the Nazi regime. In the CSF it is asked what abilities the person had 2 weeks ago, the current condition is not to be assessed, the person must be over 65 years old. There must always be a full assessment. It should be explicitly noted again that the CFS cannot be applied to individuals with early brain injury, therefore this score was not applied to this patient and is provided here only for completeness.Since the 1960s, the patient and his twin brother have been living in a residential community for disabled people and taking an active part in life. Two weeks earlier, an outbreak of SARS‐CoV2 occurred in this nursing home, with 37 out of 62 residents testing positive to the virus. This outbreak resulted in seven hospitalizations with COVID‐19 pneumonia. Two residents required treatment in the intensive care unit, and one resident died. The patient's twin brother complained of only mild symptoms of diarrhea and nausea, which improved rapidly after symptomatic therapy.Despite the patient's advanced age and his comorbidities was the patient's wish, which was brought by his niece who was caring for him, regarding on full intensive care treatment, including possible intubation, ventilation, hemofiltration, and veno‐venous extracorporeal membrane oxygenation (ECMO). Of course, we fully supported his will give his previously good quality of life and the repressions he had experienced during the Nazi regime. There was to be no euthanasia or triage based on biological age or disabilities that the patient had managed well since childhood.2 was 88% with a respiratory rate of 40/min and a paO2 of 58.8 mmHg under HFNC 90% FiO2 and 50 L/min. Both, chest radiography and native CT chest radiography showed bi‐pulmonary infiltrates that already occupied 70% of the lung parenchyma and increased rapidly during the course  and a Shaldon‐hemodialysis‐catheter into the left internal jugular vein resulted in the development of an ipsilateral pneumothorax on the same side; this mantle pneumothorax was treated conservatively and resorbed without consequence. An attempt at dilated tracheostomy was unsuccessful due to anatomic reason, and the patient was eventually extubated successfully, 16 days after intubation.He was transferred to the intensive care unit on the second day after admission to the hospital. There, SpOe Figure . The patTherapy with dexamethasone, already initiated in the emergency department, was continued for a total of 8 days; administration of immune plasma was not indicated because the patient already had an immunocompetence of 281 AU/mL SARS‐CoV2 IgG after vaccination, which increased to 722 AU/mL by the time of discharge. The initial cycle‐threshold (CT) of the RT‐PCR was 20.5 and increased to 38.1 twenty‐one days after admission to the hospital. Anticoagulation was performed with heparin, and a target PTT of 50–60 s was aimed for.Escherichia coli was detected in tracheal secretions and regressed with antibiotic therapy with Piperacillin/Tazobactam. Central line bloodstream infection caused by Streptococcus epidermitis was treated with Linezolid as tested. The time course of the infection parameters C reactive protein (CRP) and procalcitonin (PCT) under anti‐infective therapy are shown in Figures Bacterial superinfection with The patient also suffered from an acute prerenal renal failure based on a pre‐existing chronic renal insufficiency. The reason for this exacerbation was immense fluid loss due to diarrhea and vomiting associated with the COVID‐19 infection. Initial fluid therapy was able to improve renal function. However, due to continually worsening pulmonary function from COVID‐19, fluid intake had to be kept restrictive as the disease progressed. This again led to exacerbation of the acute renal failure, which was successfully treated temporarily for 5 days with continuous veno‐venous hemodialysis (cvvHD) under calcium citrate anticoagulation. After this adjuvant therapy, urea and creatinine again showed the same values as before the COVID infection Figures  and 5.Forty‐six days after admission to the hospital and 28 days after extubation the patient could be transferred from intensive medical therapy to geriatric rehabilitation. From there, the patient was transferred back to his nursing home after additionally 21 days. The Barthel index was increased from 5 to 60 points during rehabilitation, which corresponded to the patient's approximate baseline score. The patient is living again in his facility with the same quality of life than before his COVID‐19 disease.3In this case report, we describe the medical history of a 90‐year‐old man who suffered from severe COVID‐19, caused by the SARS‐CoV2 variant B1.1.7. He additionally suffered several severe complications during hospitalization, and had multiple age‐related pre‐existing conditions. Due to peripartum rhesus incompatibility reaction, he also suffered from infantile hypoxic brain injury.Since the last years, the medical possibilities in intensive care medicine have expanded remarkably and, of course, it can and must be discussed to what point which therapy is useful in each individual case. Often the opinions of the treating physicians, the nursing staff but also the relatives are diametrically opposed. Despite the ability to express their preference, more than 70% of seriously ill hospitalized elderly patients do not discuss their preferences with the healthcare provider. However, especially very elderly patients are rarely asked by the medical staff about their prior wishes and preferences. This might result in medical orders or invasive life‐sustaining therapies which are incongruent with the patients previously stated wishes and preference because the focus is deviated from comfort and quality of life.The aim of intensive therapy is to restore organ function that is threatened or lost due to illness and to bridge the organ function restriction with intensive therapy until its function is restored. Of course, especially in the case of severe disease progression, residuals can occur due to the disease itself or due to the necessary invasive therapy measures with side effects and complications, which have a negative impact on the quality of life. In older patients in particular, however, there is often a willingness to accept functional limitations. In an interesting study 20 years ago, Graf and colleagues tracked the quality of life of 153 patients with cardiovascular and pulmonary diseases after intensive care. They determined the quality of life 1 week before admission, 1 month after discharge and 9 months after discharge using the Medical Outcome Survey Short Form‐36 (SF‐36). Irrespective of the severity of illness and organ dysfunction at admission, quality of life had returned to at least baseline values in all patients after 9 months.Another secondary result of the study is particularly interesting with regard to the above‐mentioned skepticism about intensive care in older patients. Only 36 patient (21%) recalled pleasant or dreadful memories toward the ICU stay, 25 (15%) had no memories, 68 (39%) had neutral memories and 44 (25%) had pleasant memories. The majority of patients (91%) would—if necessary—approve ICU admission again.One of the most important challenges for the intensivist is the allocation of scare intensive resources to those patients who will benefit from intensive care therapy.In general, admission to the intensive care unit requires, first, the patient's desire for treatment and, second, the medical necessity and meaningfulness of the treatment. However, there is still no pre‐emptive score for any severe disease that can reliably predict the intensive care outcome in an individual patient. Therefore, the intensive care physician can only talk about the probability of occurrence of both positive aspects such as a good outcome and negative aspects such as complications and side effects. But it seems all the more important to talk to our patients or their relatives in order to find out what the patient wishes and preferences are. Even patients and their relatives should ideally discuss in advance of a life‐threatening illness if in occurrence of a severe illness invasive intensive care or comfort care is desired.Luckily, in this case, the patient's wish was clearly stated by the niece who looked after him. As, almost without exception, most countries around the world did not have clear legal guidelines for prioritizing limited intensive care resources at the time of our patient's admission, this case was handled according to the wishes of the patient and his relatives. Although based on the severity of the COVID‐19 disease, the age, the previous illnesses and the frailty, in this case a negative outcome of the disease was more likely. We cannot judge if the previous repression in his early childhood probably played an unconscious role in the decision making of the medical staff. However, during the entire stay in intensive care, despite various setbacks and complications, no therapy limitations or changes in the therapy goals were considered. The positive outcome of the patient after this long and difficult course of the disease was correspondingly gratifying for the medical treatment team.In the course of the pandemic, some countries have issued guidelines on how to proceed in the event of triage. In the UK, for example, a guideline was developed by the National Institute for Health and Care Excellence that recommended the use of the clinical frailty score for all patients on admission.Fortunately, there are now clearer guidelines in many countries, such as Germany, for a possibly necessary priority situation in the context of a resource imbalance. Here, for example, the allocation decision may only be made on the basis of the current and short‐term survival probability of the patients concerned, irrespective of disability, age, remaining life expectancy, and other characteristics.Several retrospective analyses showed in patients tested positive for SARS‐CoV‐2 that higher age and frailty are associated with a higher in‐hospital mortality.The CFS can be used in particular together with a comorbidity assessment to identify the risk of a severe course of COVID‐19 disease in older patients in order to then provide these patients with multi‐dimensional and effective medical care and interventions in order to ultimately improve the outcome of this particularly vulnerable group.4This case report can be seen as a first confirmation of Holm and Warrington's thesisAndreas Wehrfritz: Conceptualization; data curation; writing – original draft; writing – review and editing. Joachim Schmidt: Data curation; investigation; writing – original draft; writing – review and editing. Frank Bremer: Formal analysis; validation; writing – original draft; writing – review and editing. Anne‐Katharina Lang: Conceptualization; data curation; writing – review and editing. Jacob Welzer: Conceptualization; data curation; writing – original draft. Ixchel Castellanos: Formal analysis; supervision; validation; writing – original draft; writing – review and editing.We acknowledge financial support by Deutsche Forschungsgemeinschaft and Friedrich‐Alexander‐Universität Erlangen‐Nürnberg within the funding programme “Open Access Publication Funding.”The authors declare that they have no financial or personal conflicts of interest associated with this case report.The ethical approval was not required for the case report.Written informed consent was obtained from the patient's caregiver (niece) for publication of this case report.


Human papillomavirus type 7 (HPV7) is frequently found in butchers' warts and has been demonstrated in several warts of immunocompromised hosts. HPV7 is rarely identified in non‐butchers' warts, especially in individuals with normal immune status. We describe the first case of multiple HPV7‐induced digitated warts which were developed on the face of a 68‐year‐old Japanese man, whose immune status was normal and who had no history of meat handling. Interestingly, the warts were developed exclusively on the skin affected with seborrhoeic eczema in the face, suggesting that some biologically active factors associated with seborrhoeic eczema and anatomical factors of sun‐exposed facial skin might contribute to the development of HPV7‐induced warts. Human papillomavirus type 7 (HPV7) is frequently found in butchers' warts and has been demonstrated in several warts of immunocompromised hosts. We reported the first case of multiple HPV7–induced digitated warts on the seborrhoeic eczema of the face, a sun–exposed area, of a non–butcher immunocompetent individual. In present case, UV exposure might contribute to the activation of the promotor of HPV7 in the face, a sun–exposed area. The papules were developed initially on the forehead and gradually spread to both nasolabial folds of the face.He was employed as an engineer in telephone equipment and had never worked as a meat handler. He had no different sexual partners including some homosexual contacts in the past. Result of scrutiny, a pathological condition leading to immune‐compromised was not found. He had no history of malignancy.Clinically, peculiar verrucous papules of 5–7 mm diameters showed exophytic growth in the face, with spiky and hyperkeratotic surfaces to be diagnosed with the digitated wart. Interestingly, the verrucous papules developed exclusively on the scaly and erythematous skin lesions diagnosed with seborrhoeic eczemaAfter informed consent was obtained, two biopsies were taken from a verrucous papulae of the face and scaly erythema surrounding the papulae under local anaesthesia with the diagnosis of the digitated wart and seborrhoeic eczema.Histological examination with haematoxylin and eosin (HE) stain showed the verrucous papulae to be a common wartImmunohistochemically, using avidin‐biotin‐peroxidase complex (ABC) methodHPV polymerase chain reaction (PCR) in the extracted DNA from the wart  was performed with the specific primers allowing the detection of the five main skin‐related HPV types  ; Data curation (Lead); Formal analysis ; Investigation ; Methodology ; Project administration ; Resources ; Validation (Lead); Visualization ; Writing – original draft (Lead). Masaaki Kawase: Conceptualization (Supporting); Data curation (Supporting); Formal analysis ; Investigation ; Methodology ; Project administration ; Resources ; Supervision (Lead); Validation (Supporting); Visualization ; Writing – review & editing (Supporting). Kiyofumi Egawa: Supervision (Supporting); Writing – review & editing (Lead).We confirmed the patient consent for the publication of all case reports and all clinical images, and that appropriate consent has been obtained.


Local healthcare systems were found to conceptualise health inequalities in a vague and varying manner, and their conceptualisations did not reflect established health inequalities frameworks. A clear conceptual national framework for addressing health inequalities is needed to support local healthcare systems, so they can address health inequalities meaningfully and sustainably.In 2019, local healthcare systems in England were asked to develop formal plans to reduce health inequalities. Here, we explore plans to understand how local healthcare systems conceptualise health inequalities and why. A broad Internet search and targeted search of NHS websites were conducted to identify all publicly accessible healthcare planning documents  Long‐Term Plan (LTP) response documents) produced by local health partnerships in England. A thematic document analysis of the accessible plans was undertaken in NVivo by coding text relating to health inequalities. Of the 44 documents developed, 13 were publicly accessible. These 13 local plans were submitted to NHS England for review between September 2019 and January 2020 and averaged 167 pages (range: 41–273 pages). Only one document contained a chapter dedicated to health inequalities. After analysis, five themes were identified: (1) v Inequalities in health outcomes and care are widening in many instances, particularly as a result of the COVID‐19 pandemic.Healthcare systems are being increasingly tasked with addressing health inequalities.There is currently little research exploring how local healthcare systems conceptualise and approach health inequalities.Based on planning documents, local healthcare systems in England were found to conceptualise and approach health inequalities in a manner that was vague and inconsistent.There appeared to be a use of value judgements, lack of prior conceptualisation and a lack of commitment to concrete action to reduce inequalities.A clear conceptual national framework for addressing health inequalities is needed to support local healthcare systems.1Despite health inequalities being a priority for many countries, the gap in access and quality of healthcare and health outcomes between the most and least disadvantaged groups is widening in many cases  and integrated care systems (ICSs) , October 2019 (n = 1), November 2019 (n = 4), December 2019 (n = 1) and January 2020 (n = 1), with the remaining plans (n = 2) not specifying their publication date. The average length of the plans was 167 pages (range: 41–273 pages) and there was good geographical coverage across a broad range of England’s local health organisations such as STPs and ICSs. Of the 13 plans analysed, four contained a chapter addressing health inequalities and prevention and one contained a chapter dedicated solely to health inequalities. The remaining documents combined plans to address health inequalities with more generic plans for prevention or had their health inequalities plan scattered throughout in multiple places within the documents.Thirteen documents were found from a possible 44. The plans were published in September 2019 ‘By March 2024, the target populations identified in the health and well‐being strategy will be prioritised for action across the System… Improvements in health outcomes should be occurring greater pace in this group than the general population to enable reductions in health inequalities’.. Terms found within the plans that came up most often in reference to health inequalities but were used vaguely included ‘health inequality’, ‘outcome’, ‘vulnerable’, ‘hard to reach’ and ‘disadvantaged’. For example, the quote below highlighted the need for improvements in health outcomes to reduce inequalities but did not detail which outcomes these are:These instances provided evidence that the local response plans acknowledge the LTP’s request to address health inequalities but reflected a superficial conceptualisation by local healthcare systems.Plan J)‘Variation in practice will be removed and efforts directed towards tackling inequalities by focusing on vulnerable groups and those who experience the poorest health outcomes. For example, increasing breastfeeding rates is one of the simplest ways of reducing health inequalities and benefits both women and babies’.‘Around one in five adults in [Plan A] smoke, but this increase to at least one in four in the most deprived neighbourhoods as well as in high‐risk groups ’. (Plan B)‘The council and partners recognise the central importance of evidence‐based parenting support in ensuring school readiness, especially within deprived populations and high‐risk groups and a set of outcome‐based KPIs have been agreed to ensure progress in this area’., people with mental health problem, black men, rough sleepers and individuals with a disability. Examples of this included:Plan E)‘Life expectancy varies between our six local places and also within our neighbourhoods’.(Plan K)‘There is a higher number of premature deaths of people with serious mental health problem compared to the national average’.‘Meet continuity of carer targets of 35% by March 2020, 51% in 2021 and 75% in 2024 for BAME women and those most vulnerable’.(Plan M)‘Reduce current variation and inequalities in delivery and health outcomes’.. Most plans made minimal or no use of metrics and indicators to set clear goals for themselves, whilst others were more specific. For example:3.23.2.1Plan K)‘Improve recording of ethnicity and other protected characteristics in NHS patient records’ in an effort to gather more data surrounding health inequalities experienced by BAME populations in order to reduce them.‘The Medicines Optimisation and Pharmacy Transformation (MOPT) programme will work with all health and social care professionals to ensure…Easy access to health and medicines advice to empower residents and patients to control their own health or disease, reducing health inequalities’.‘By 2023/24, we will put in place initiatives to tackle health inequalities, with a particular focus on social value, the environment and volunteering’.‘Invest levels of resources in developing and implementing a [Plan C] Healthy Lives programme to improve health, reduce health inequalities and reduce the growth in demand for health and care services’. have had a statutory responsibility for the past 6 years to address health inequalities. This, therefore, suggested a lack of prior consideration of health inequalities.Since the response plans were written to be reviewed by a central healthcare organisation and the language of the plans reflected that of national policy, it is possible that the local healthcare organisations were more focused on using language that would be acceptable to those evaluating the plans, rather than setting out a bold and ambitious plan. This may reflect the dynamic between regional structures and local health systems, whereby local health systems try to mitigate the disruptive impact of national and regional policies on their local priorities.Another explanation for the vagueness of the local plans is the vagueness of the national LTP document. The national plan itself was lacking in detail, making it less surprising that the subsequent local plans are vague and varied. For example, the National Implementation Framework for the LTP states that an ‘inequalities reduction trajectory’ will be used to monitor the reduction of health inequalities NHS, . It is nVagueness could have also been due to the value judgement inherent in the definition of health inequalities. These value judgements may be influenced by a strong presence of patient advocates and local champions and the conceptualisation of health inequalities as both the health of marginalised groups (e.g. LGBTQ+) and health changing according to a socio‐economic gradient. This raises the question of what a ‘fair’ inequality is and why some groups are consequently thought of as more ‘deserving’ of ill‐health than others. This mentality only works to perpetuate discriminatory stigma surrounding certain groups which is in of itself unfair.Whilst a lot of plans did mention social determinants as a cause of health inequality, the plans focused more on self‐management of health, behavioural and lifestyle changes and quality of care; this placed the burden on the individual and focused on a reactive rather than preventative approach. A possible explanation for this focus is that local health systems feel powerless to address the social determinants of health on their own since it requires a collaboration between various cross‐governmental agencies. Emphasising a reactive and lifestyle‐behavioural approach should be cautioned against since it may perpetuate the idea that certain groups are unhealthy because of personal choice.Lastly, variation across the documents may be useful because it allows for local healthcare systems to determine their own priorities. However, there is a risk that groups with stronger advocate presence are given more attention or higher value judgements, rather than allocating attention based on data‐driven levels of need. For example, the documents prioritise learning disabilities and severe mental illnesses compared to immigrants, refugees, asylum seekers, those with prior justice system involvement and LBGTQ+populations to which little attention was given.4.4In terms of the national plan to reduce health inequalities, the findings of this study were in line with criticisms that the plan is vague in scope and lacking in direction to reduce health inequalities (Ford et al., It has been argued that the case for groups experiencing inequalities have to be ‘sold’ to non‐academics and policy makers in order for action to be taken, an idea that is in line with our theme of use value judgements (Garthwaite et al., 4.5Based on this analysis, we have published a complementary paper which unpacks the concept of health inequalities for local health systems. It sets out to frame inequalities to ensure a systematic and logical approach in health systems, build on long‐term organisational change and redistribute resources and power to prevent illness and promote health (Ford et al., National conceptualisation needs to go hand in hand with clear guiding principles about how to reduce inequalities. These principles should include the dimensions of inequalities local healthcare systems should consider, and the measures such systems can use to monitor the reduction of inequalities within their jurisdictions. An upskilling of healthcare system decision makers is also needed to promote a more developed approach to inequalities.A framework also needs to be part of a partnership between multiple governmental bodies to form a wider cross‐government health inequalities strategy to tackle the social determinants of health inequalities (Marmot et al., In summary, local healthcare systems conceptualise health inequalities in a vague and variable manner. This may be the result of a lack of prior conceptualisation and approach to understanding of health inequalities, use of value judgements on what fair and unfair health inequalities are and a lack of commitment to take action to reduce health inequalities. These results suggest that the development of an agreed national conceptual framework to guide policy makers and local healthcare decision makers is required to understand and reduce health inequalities.The authors have no conflicts of interest or relationship, financial or otherwise, to declare that might be perceived as influencing the objectivity or our work.The authors confirm contribution to the paper as follows: study conception and design: J. Ford, J. Olivera; data collection: J. Olivera; analysis and interpretation of results: J. Olivera, J. Ford, S. Sowden, C. Bambra; draft manuscript preparation: J. Olivera, J. Ford, S. Sowden, C. Bambra. All authors reviewed the results and approved the final version of the manuscript.Supplementary MaterialClick here for additional data file.


The use of tranexamic acid for postpartum hemorrhage has entered obstetrical practice globally with the evidence‐based expectation of saving lives. This improvement in the care of women with postpartum hemorrhage has come at a price. For the anesthetist, having tranexamic acid ampoules close at hand would seem an obvious strategy to facilitate its use during cesarean delivery, an important setting for severe hemorrhage. Tragically, we have identified a number of recent instances of inadvertent intrathecal administration of tranexamic acid instead of local anesthetic for spinal anesthesia. Reported cases of this catastrophic error seem to be increasing. The profound neurotoxicity of tranexamic acid causes rapid‐onset convulsions, with mortality of 50%.How can these tragic errors be averted? Drug safety alerts have been issued by the US Food and Drug Administration and the World Health Organization, but that is not enough. We recommend extensive dissemination of information to raise awareness of this potential hazard, and local hospital protocols to ensure that tranexamic acid is stored separately from anesthetic drugs, preferably outside the operating room and with an auxiliary warning label. Implementation of safety strategies on a very large scale will be needed to ensure that the life‐saving potential of tranexamic acid is not eclipsed by drug‐error mortality. Increasing use of tranexamic acid during cesarean delivery has been associated with fatal erroneous intrathecal administration. Tranexamic acid should not be stored on or near the theatre anaesthetic trolley.The World Health Organization recommends tranexamic acid (1‐g) intravenously over 10 minutes, within 3 hours, for treating postpartum hemorrhage (PPH), unless contraindicated.The implementation of this recommendation, intended to improve the care of women with PPH, has exposed an unanticipated but important risk associated with increasing tranexamic acid use within obstetricalcare. The profound toxicity of intrathecal tranexamic acid was described in 1980.This potential drug error was highlighted, and recommendations to prevent it outlined in a 2019 publication following the identification of a fatal case through a South African confidential inquiry into maternal deaths.In South Africa, most specialist‐led anesthetic departments in large hospitals have well‐established protocols for drug checking during spinal anesthesia. In smaller hospitals, however, spinal anesthesia is typically administered by generalist medical officers who do not work within the structure of an anesthetic department and may not always be aware of the necessity for meticulous drug identification checks. The situation may be similar in many low‐middle–income countries, where anesthetics are often administered by a variety of healthcare cadres. Although a lack of specialist oversight may increase the risk for anesthesia‐related drug errors, drug errors owing to failure to follow guidance on the safe and secure handling of medicines can occur at any level of hospital, government‐run or private, in any part of the world.Prophylactic use of tranexamic acid at cesarean delivery has been shown to be associated with reduced blood loss >1000 ml, but not reduced mortality or severe morbidity.1Informing anesthetic practitioners and managers of the dangers of intrathecal tranexamic acid using various formats  through various channels, including:▪World Health Organization Box 9▪National regulatory authorities Box 10▪Pharmaceutical services managers▪Healthcare training institutions▪Professional societies▪Outreach and regional clinicians▪National or regional clinical guideline documents9Drawing up local risk management strategies and protocols for hospital health practitioners and managers related to the use of tranexamic acid, aimed at minimizing the risk of inadvertent intrathecal administration and enhancing patient safety:▪Tranexamic acid must always be stored separately from anesthetic drugs used in the operating room, in a secure container away from the anesthetic drugs trolley.▪Tranexamic acid must never be put on the spinal anesthetic trolley that is set up in preparation for administering a spinal anesthetic.▪Anesthetic practitioners need to carefully read the label each time before a drug for spinal anesthesia is drawn up, rather than relying on visual recognition or location of the drug ampoules.▪3Implementing the following protocols:If the hospital has a look‐alike, sound‐alike (LASA) list of medications,▪Effective implementation of the strategies and protocols above across all hospitals in a region will require oversight with regular communication and audit of practice by a regional clinical or administrative supervisor.▪For countries where tranexamic acid is being introduced for use in obstetrics for the first time, it is important that the introduction incorporates information about the risk and consequences of inadvertent intrathecal administration (step 1 above) and recommendations regarding protocols to minimize risk of the drug error occurring (step 2 above).We recommend the following urgent steps to eliminate the severe and life‐threatening consequences of intrathecal administration of tranexamic acid at all hospitals where intravenous tranexamic acid is available:Box 1World Health Organization AlertIn 2022 the World Health Organization (WHO) issued an alertIntrathecal tranexamic acid is a potent neurotoxin and neurological sequelae are manifested, with refractory seizures and 50% mortality. The profound toxicity of intrathecal tranexamic acid was described in 1980. A 2019 review identified 21 reported cases of inadvertent intrathecal injection of tranexamic acid since 1988, of which 20 were life‐threatening and 10 fatal. Sixteen were reported between 2009 and 2018.WHO recommends early use of intravenous tranexamic acid within 3 hours of birth in addition to standard care for women with clinically diagnosed PPH following vaginal births or caesarean section. Tranexamic acid should be administered at a fixed dosage of 1 g in 10 ml (100 mg/mL) IV at 1 ml per minute, with a second dosage of 1 g IV if bleeding continues after 30 minutes.Tranexamic acid is frequently stored in close proximity with other medicines, including injectable local anesthetics indicated for spinal analgesia . The presentation of some of the local anesthetics is similar to the tranexamic acid presentation (transparent ampoule containing transparent solution), which can erroneously be administer instead of the intended intrathecal anesthetic resulting in serious undesirable adverse effects.Recently, obstetricians from several countries have reported inadvertent intrathecal tranexamic acid administration and related serious neurological injuries.Tranexamic acid is a lifesaving medicine, however, this potential clinical risk should be considered and addressed by all operating room staff. Reviewing of existing operating room drug handling practice is required to decrease this risk, such as storage of tranexamic acid away from the anesthetic drug trolley, preferably outside the room.”US Food and Drug Administration AlertIn 2020 the US Food and Drug Administration (FDA) issued an alertStore tranexamic acid injection vials separately from other drugs, in a way that makes the labels visible to avoid reliance on identifying drugs by the vial cap color.Add an auxiliary warning label to note that the vial contains tranexamic acid.Check the container label to ensure the correct product is selected and administered.Utilize barcode scanning when stocking medication cabinets and preparing or administering the product.”Careful handling of tranexamic acid injection is important to prevent medication errors that could result in serious injury or death. Healthcare professionals should consider the following steps:PPH, postpartum hemorrhage.Moran. Tranexamic acid at cesarean delivery: drug‐error deaths. Am J Obstet Gynecol 2022.Creative solutions are needed to ensure access for women with PPH to life‐saving therapy with tranexamic acid while guarding against the risks of mortality from drug administration errors. Regulatory bodies, suppliers, and manufacturers also have an important role in resolving this problem, for example by ensuring that tranexamic acid drug ampoules carry clear warning labels about the correct route of administration. A coordinated international effort is required to prevent inadvertent intrathecal tranexamic acid administration.The authors report no conflict of interest.


Landscape structure plays a key role in mediating a variety of ecological processes affecting biodiversity patterns; however, its precise effects and the mechanisms underpinning them remain unclear. While the effects of landscape structure have been extensively investigated both empirically and theoretically from a metapopulation perspective, the effects of spatial structure at the landscape scale remain poorly explored from a metacommunity perspective. Here, we attempt to address this gap using a spatially explicit, individual‐based metacommunity model to explore the effects of landscape compositional heterogeneity and per se spatial configuration on diversity at the landscape and patch levels via their influence on long‐term community assembly processes. Our model simulates communities composed of species of annual, asexual organisms living, reproducing, dispersing, and competing within grid‐based, fractal landscapes that vary in their magnitude of spatial environmental heterogeneity and in their degree of spatial environmental autocorrelation. Communities are additionally subject to temporal environmental fluctuations and external immigration, allowing for turnover in community composition. We found that compositional heterogeneity and spatial autocorrelation had differing effects on richness, diversity, and the landscape and patch scales. Landscape‐level diversity was driven by community dissimilarity at the patch level and increased with greater heterogeneity, while landscape richness was largely the result of the short‐term accumulation of immigrants and decreased with greater compositional heterogeneity. Both richness and diversity decreased in variance with greater compositional heterogeneity, indicating a reduction in community turnover over time. Patch‐level richness and diversity patterns appeared to be driven by overall landscape richness and local mass effects, resulting in maximum patch‐level richness and diversity at moderate levels of compositional heterogeneity and high spatial autocorrelation. The role of landscape spatial structure in shaping biodiversity patterns remains poorly explored from a metacommunity perspective. We used an individual‐based metacommunity model to investigate the effects of compositional heterogeneity and spatial configuration on biodiversity via their effects on community assembly. We show that different degrees of compositional heterogeneity and spatial autocorrelation result in different assembly processes predominating and that richness and diversity are shaped by different processes at the landscape and patch scales, resulting in differing responses to compositional heterogeneity and spatial autocorrelation at different scales. Spatial distributions for the two patch attributes were generated via an R implementation of the spatially autocorrelated landscape generation algorithm from Saupe , Tpatch and Hpatch are the temperature and habitat values for a given patch. Reproductive output is additionally limited by a trade‐off between tolerance and maximum expected offspring, meaning that organisms with broader tolerances produce fewer offspring on average. This trade‐off serves to prevent organisms from having infinitely large tolerances. The strength of this trade‐off is determined by the trade‐off parameter α  and eight different G  scenarios . We ran each scenario over a set of 10 different landscapes, doing three simulation runs for each landscape, resulting in a total of 30 individual runs for each scenario. The model parameters for our simulations are summarized in Table Landscapes were initialized from text files containing the respective 2.7G, Hurst index, landscape, and replicate to reduce computation time. We assessed landscape‐level patterns via the distribution of landscape richness and Shannon–Weiner diversity between the 5000th and 10,000th time steps and patch‐level patterns via the distribution of patch richness and Shannon–Weiner diversity at the end of the simulation.Data visualization was performed in R 3.6.3 , around which it fluctuates. Species richness and Shannon–Wiener diversity index responded at both the landscape and patch levels to both compositional heterogeneity and spatial autocorrelation, with differing responses occurring at the landscape and patch levels Figures  and 3. A4G) and spatial autocorrelation (Hurst index) had differing effects at the landscape and patch levels, resulting from different processes acting at different scales. Landscape‐level diversity in this model resulted from community dissimilarity at the patch level due to greater environmental heterogeneity and a more fragmented spatial configuration. This finding aligns with the predictions of the dominance of diversity hypothesis ; data curation (lead); investigation (lead); methodology (lead); software (lead); visualization (lead); writing – original draft (lead). Thomas Hovestadt: Conceptualization ; funding acquisition (lead); investigation (supporting); methodology (supporting); project administration (lead); supervision (lead); visualization (supporting); writing – review and editing (supporting).https://www.landklif.biozentrum.uni‐wuerzburg.de/) funded by the Bavarian Ministry of Science and the Arts via the Bavarian Climate Research Network (Bayklif). This publication was supported by the Open Access Publication Fund of the University of Würzburg.This study was conducted within the framework of the joint project Landklif (Data S1.Click here for additional data file.Data S2.Click here for additional data file.


To evaluate the impact of embryo banking on the cumulative live birth rate (CLBR) and the time to live birth (TTLB) in poor ovarian responders (POR) according to the Bologna criteria.n = 121) or without (n = 155) embryo banking at the discretion of the attending physicians. A total of 656 and 405 stimulation cycles were started in the two groups respectively during the 24 month follow‐up.A total of 276 infertile women undergoing IVF with POR were included in this retrospective study. They were divided into two groups with (p > 0.05). The CLBR was significantly lower in the banking group than in the non‐banking group (31.4% (38/121) and 43.2% (67/151), p < 0.05). TTLB was significantly longer in the banking group . In the Kaplan–Meier analysis, the cumulative incidence of live birth was significantly lower in the banking group compared with the non‐banking group .The biochemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth rate per transfer were comparable between two groups (Embryo banking in women undergoing IVF with POR based on the Bologna criteria reduces CLBR and lengthens TTLB when compared with no embryo banking. A retrospective cohort study of 276 infertile women undergoing IVF with poor response according to the Bologna criteria revealed embryo banking reduces the cumulative live birth rate and lengthens the time to live birth. Thus, the aim of this retrospective study was to compare the cumulative live birth rate and time to live birth (TTLB) between women undergoing IVF with POR according to the Bologna criteria in a 24 month follow up who had either embryo banking or no embryo banking. We hypothesized that embryo banking improved the cumulative live birth rate in women with POR.22.1The study protocol was approved by the Institutional Review Board of the hospital (No. KS20163). Informed consent was waived because only unidentified data were used in this retrospective study.Infertile women who underwent IVF in our center between October 2016 and March 2020 were included for this retrospective study if they had at least two of the following three features according to the Bologna criteria: (i) advanced maternal age (≥40 years) or any other risk factors for POR ; (ii) a previous POR ; and (iii) an abnormal ovarian reserve test  less than 5–7 follicles and serum anti‐Mullerian hormone (AMH) less than 0.5–1.1 ng/mL). Women were excluded if they were: (i) aged ≥46 years, (ii) having an abnormal uterine cavity shown on hysterosalpingogram or hysteroscopy, (iii) having moderate or severe endometriosis, (iv) using donor eggs/sperm, (v) undergoing pre‐implantation genetic testing, (vi) on adjuvant therapy, such as dehydroepiandrosterone and growth hormone. Each patient were followed up for 24 months from the first day of ovarian stimulation in the first IVF cycle.Women were offered either embryo banking or no banking at the discretion of the attending clinicians or subject to the wishes of the couple after extensive counseling. In the banking group, all couples were offered several consecutive stimulation cycles until at least five frozen embryos were banked prior to embryo transfer , mild stimulation and natural cycle at the discretion of the attending clinicians. For the long protocol, 1.25 mg GnRH agonist  was given for pituitary desensitization from the mid‐luteal phase in the previous cycle. On Day 2–3 of the menstrual cycle they underwent transvaginal ultrasound examination and serum estradiol measurement. hMG  or FSH  was given at 225–300 IU per day based on the antral follicle count (AFC), age of the woman, body mass index (BMI) and previous ovarian response, according to the standard operating procedures of the center. Ovarian response was monitored by serial transvaginal scanning with or without hormonal monitoring. Further dosage adjustments were based on the ovarian response at the discretion of the clinicians in charge. For the antagonist protocol, antagonist 0.25 mg daily  was given from the sixth day of ovarian stimulation until the day of ovulation trigger. For the PPOS protocol, medroxyprogesterone  was given on the same day together with hMG or FSH stimulation. Mild stimulation was used by given clomifene citrate 100 mg for 5 days followed by hMG 150 IU per day until the day of ovulation trigger.When 1–3 leading follicles reached ≥18 mm in diameter, triptorelin  and hCG  or Ovidrel 250 microgram  were given to trigger final maturation of oocytes. Oocyte retrieval was performed around 36 hours following the ovulatory trigger.2.35 after washing or normal morphology was <1%, intracytoplasmic sperm injection (ICSI) was performed. Oocytes were decoronated and checked for the presence of two pronuclei to confirm fertilization. Embryos were graded on day 3 after retrieval as grade one to grade six according to the evenness of each blastomere and the percentage of fragmentation.About 2 h after oocyte retrieval, each oocyte was inseminated with approximately 20 000–30 000 motile spermatozoa. If the total number of motile sperm was <102.4In the non‐banking group, 1–2 fresh embryos were transferred on Day 3 after retrieval under transabdominal ultrasound guidance. Surplus day 3 embryos or day 5 or 6 blastocysts in the non‐banking group and all viable embryos/blastocysts in the banking group were vitrified. Those who did not get pregnant in the stimulated IVF cycle and those who postponed fresh transfer would undergo FET at least 2 months after the stimulated cycle. The details of vitrification and warming procedure are described elsewhere.2.5The primary outcome measure was the cumulative live birth rate (CLBR) of which the ongoing status had to be achieved within 24 months since the first day of ovarian stimulation in the first stimulation cycle. In addition, LBR was calculated by including the first live birth generated during the 24 months period whether via fresh or FET cycles. Secondary outcome measures included time to live birth measured as the time from the first day of ovarian stimulation in the first cycle to a live birth, number of stimulation cycles per woman, total number of oocytes obtained per woman, number of cycles canceled before oocyte retrieval, number of patients with no embryo for transfer, number of started cycle with no embryo for transfer, number of transfer cycles in both group; number of oocytes obtained, fertilized per retrieval, number of transferable embryos per retrieval, and total number of transferable embryos per woman. Clinical pregnancy, biochemical pregnancy (defined as a positive pregnancy test), ongoing pregnancy, miscarriage, multiple pregnancy, and implantation rates per transfer in both fresh and FET cycles, time to ongoing pregnancy/live birth were also compared.A baby born alive after 22 weeks gestation was classified as a live birth. Clinical pregnancy was defined as the presence of at least one gestational sac on ultrasound at 6 weeks. Ongoing pregnancy was the presence of at least one fetus with heart pulsation on ultrasound beyond 10 weeks. Implantation rate was calculated as the number of gestational sacs seen on scanning divided by the number of embryos replaced. Miscarriage rate was defined as the number of miscarriages before 22 weeks divided by the number of women with clinical pregnancy. Cancellation rate was defined as number of patients with no viable embryo to transfer divided by number of patients that started ovarian stimulation.2.6t‐test, Mann–Whitney U test for continuous variables and chi‐square test for categorical variables, where appropriate. The Kaplan–Meier (KM) method was used to calculate the cumulative proportion of ongoing pregnancies leading to live births, and time to pregnancy was graphically depicted by cumulative incidence curves. The log‐rank test was used to measure whether significant differences existed in the cumulative incidence curves. Censored data were considered when patients did not return for treatment. Women who did not reach the primary outcome (live birth) including those achieving a continuing pregnancy that did not lead to live birth were also censored. A Cox proportional hazard model was used to evaluate the relative prognostic significance of independent variables in relation to CLBR.Continuous variables are given as the mean ± SD if normally distributed, and as the median + interquartile range if not normally distributed. Statistical comparison was carried out by Student's p < 0.05 was considered statistically significant.Statistical analyses were performed using the Statistical Program for Social Sciences . The two‐tailed value of 3A total of 326 women were screened, out of 276 women who met the selection criteria, 121 women had embryo banking while 155 women had no embryo banking. A total of 656 and 405 stimulation cycles were started in the banking and non‐banking group respectively within 24 months follow up . Medians for survival (live birth) time in non‐banking group was 17.5 (95%CI 12.8–22.2) months, while in the banking group, no more than half of the patient reached a live birth within 24 months follow up.The CLBR was significantly lower in the non‐banking group compared to that in the banking group. Moreover, the average time from ovarian stimulation to live birth was significantly longer in the banking group compared to the non‐banking group. In Kaplan–Meier analysis Figure , the cump = 0.018), and number of stimulation cycles per woman was negatively associated with the CLBR , p < 0.001).Cox proportional hazard modeling Table  using th4In this retrospective study, we found that embryo banking in women undergoing IVF with POR was associated with a significantly lower cumulative live birth rate and a significantly longer time to live birth when compared with no embryo banking.p = 0.002). Additionally, the cumulative live birth rate including all embryo transfer was also significantly higher in the ‘triple freeze program’. However, the comparison was not fair as it was based on all transfers from embryos banked through three stimulation cycles versus a fresh embryo transfer following one stimulation cycle. In the present study, we included all stimulation cycles in both groups within 24 months after the first stimulation cycle.The concept of oocyte banking through repeated IVF cycles was first published by Cobo et al.Poor outcomes in the treatment of women with POR with a single IVF cycle is usually due to high cycle cancellation rates or lack of good quality embryos for transfer, and there is still no consensus on the optimal stimulation protocols for women with POR.The modern technology of vitrification allows safe cryopreservation of oocytes and embryos with a high post‐warming survival rate. The transfer of frozen embryos in the freeze‐all protocol has been reported to result in improved live birth rates when compared to fresh transfer in women with polycystic ovary syndrome or normal ovarian response.In this study, a similar number of oocytes and transferable embryos per retrieval was noted between the two groups although the two groups used different ovarian stimulation protocols. Strategies with embryo banking up to five instead of fresh transfer could allow more stimulation cycles in the same period. During 24 months follow up, patients in the non‐banking group had undergone 2.6 ± 1.5 stimulation cycles, while those in the banking group finished 5.3 ± 2.8 stimulation cycles. The banking of embryos over multiple cycles would provide a greater number of embryos for selection and transfer of better quality embryos. However, it did not improve the CLBR in women with POR. Cox regression model in our study demonstrated that the number of oocytes obtained, and number of transferable embryos per woman and number of transfer cycles were not associated with the CLBR, but the number of stimulation cycles per woman was negatively associated with the CLBR after adjusting for other confounding factors. It can be argued that multiple retrievals and cryopreservation of embryos in the banking might have incurred in a higher cost compared to that with a single stimulation cycle followed by fresh transfers. And there is an obvious advantage of avoiding further unnecessary stimulation cycles, in case that live birth is achieved in the first or second cycle. Furthermore, women in the banking group were also subject to repeated invasive retrievals procedures, which were associated with a small surgical risk.The selection criteria in our study were different from those used in previous studies. Cobo et al.The limitations of our study are its retrospective design, a small sample size and being performed at a single center, so results may not be generalizable to other populations and clinical setting. Some imbalance in characteristics were found between two groups and Cox regression analysis was carried out for controlling the bias. Another limitation might be the permitted between‐cycle regimen adjustments in both strategy since patient or physician are apt to try another stimulation protocol if the previous one failed. The number of embryos transferred were different with more women undergoing single embryo transfer in the non‐banking group as some of the patients only had one fresh embryo to transfer after one stimulation cycle. Randomized controlled trials with adequate sample size should be conducted to confirm these findings.5In conclusion, in women with a poor response based on the Bologna criteria starting their IVF/ICSI treatment, embryos banking strategy does not improve cumulative live birth rates while it prolongs time to live birth. Therefore, implement embryos banking strategy in poor responders is not effective compared to conventional non‐banking strategy.This study was supported by the Special Fund for Clinical Medical Research of Shanghai Municipal Health Commission (No: 202040127).The authors declare no conflict of interest.The study protocol was approved by the Institutional Review Board of the hospital (No. KS22357). Informed consent was waived because only unidentified data were used in this retrospective study.


Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Use of electronic health records may facilitate large‐scale epidemiologic research to elucidate risk factors for the progression of MGUS to MM or other lymphoid malignancies.We evaluated the accuracy of an electronic health records‐based approach for identifying clinically diagnosed MGUS cases for inclusion in studies of patient outcomes/ progression risk.Data were retrieved from Kaiser Permanente Southern California's comprehensive electronic health records, which contain documentation of all outpatient and inpatient visits, laboratory tests, diagnosis codes and a cancer registry. We ascertained potential MGUS cases diagnosed between 2008 and 2014 using the presence of an MGUS ICD‐9 diagnosis code (273.1). We initially excluded those diagnosed with MM within 6 months after MGUS diagnosis, then subsequently those with any lymphoid malignancy diagnosis from 2007 to 2014. We reviewed medical charts for 100 randomly selected potential cases for evidence of a physician diagnosis of MGUS, which served as our gold standard for case confirmation. To assess sensitivity, we also investigated the presence of the ICD‐9 code in the records of 40 randomly selected and chart review‐confirmed MGUS cases among patients with a laboratory report of elevated circulating monoclonal (M‐) protein (a key test for MGUS diagnosis) and no subsequent lymphoid malignancy (as described above).The positive predictive value (PPV) for the ICD‐9 code was 98%. All MGUS cases confirmed by chart review also had confirmatory laboratory test results. Of the confirmed cases first identified via M‐protein test results, 88% also had the ICD‐9 diagnosis code.The diagnosis code‐based approach has excellent PPV and likely high sensitivity for detecting clinically diagnosed MGUS. The generalizability of this approach outside an integrated healthcare system warrants further evaluation. Clinically, MGUS features moderately elevated serum monoclonal protein  and the absence of evidence of end organ damage  or amyloidosis.Overall, factors relating to the progression of MGUS to MM and other lymphoproliferative disorders remains largely unknown. Additionally, MGUS patients have demonstrated higher morbidity and mortality from bacterial and viral infections, peripheral neuropathy, thrombosis and other chronic diseases.While population‐based screening may be considered the gold standard for observational research, this approach requires the availability of archived biospecimens. For MGUS, the diagnosis is not clinically actionable at present,To build on these efforts to facilitate large scale epidemiologic research of MGUS using electronic health records—in particular, studies of factors associated with risk of progression to malignancy or other outcomes—we evaluated the performance of an electronically searchable diagnosis code‐based algorithm to identify patients with clinically diagnosed MGUS using electronic health records from a large integrated health care delivery system.22.1This study was conducted at Kaiser Permanente Southern California, a large integrated healthcare system with over 4.6 million members. Data were retrieved from the system's comprehensive electronic health records, which contain chart notes from all medical encounters , laboratory testing data and diagnosis codes, and Kaiser Permanente's Surveillance, Epidemiology and End Results‐affiliated cancer registry. The study was approved by Kaiser Permanente Southern California's Institutional Review Board, which also waived the requirement for informed consent.2.2We searched for patients with a first ICD‐9 diagnosis code of 273.1 between 2008–2014 .We excluded those with a MM diagnosis within 6 months following the record of the index ICD‐9 code.Of the potential MGUS cases identified by steps (i) and (ii), we further restricted to those with at least 1 year of continuous health plan membership prior to the date of the index ICD‐9 code for the manual chart review confirmation .We then randomly sampled 100 individuals from the remaining sample of eligible putative MGUS cases for chart review.The algorithm that we evaluated for identifying patients with clinically diagnosed MGUS had the following steps:The initial chart reviews revealed that some recorded electronic ICD‐9 codes for MGUS corresponded to a work‐up that led to diagnoses of other lymphoid malignancies , a physician diagnosis of MGUS in the chart notes was considered the gold standard for confirmation.We manually reviewed medical chart notes within (±) 6 months of the first recorded ICD‐9 code (273.1) for documentation of a physician diagnosis to confirm clinically diagnosed MGUS for the randomly selected putative cases. For any unconfirmed cases, we further conducted review of the entire medical history to understand potential reasons for the inaccuracies. All reviews and confirmation dispositions were verified by a second chart reviewer. Because our purpose was to validate the diagnosis code‐based algorithm for identifying patients with clinically diagnosed MGUS . These challenges supported our decision to rely on evidence of a physician diagnosis as the gold standard for confirming clinically diagnosed MGUS in plan members with the corresponding ICD‐9 code rather than relying on reported clinical symptoms. We initially sought to determine the timing of the physician diagnosis. However, as the chart notes often had insufficient documentation of this timing, it was rarely possible to distinguish patients with newly diagnosed MGUS from those with a history of MGUS that predated our study period.To address potential misclassification between MGUS and smoldering MM, we specifically searched the chart notes to capture potential smoldering MM diagnoses for those without a quantifiable M‐protein value . We also searched for and conducted chart review to confirm an electronic ICD‐9 code for MM diagnosis (203.0) within 2 years after the index date among all confirmed MGUS cases, as misclassified smoldering MM cases would have a higher probability than true MGUS cases of progressing that quickly after the MGUS diagnosis.2.4To estimate the sensitivity of the electronic ICD‐9 code‐based case‐identification algorithm, we used the same process described above (for the subsample of putative cases first identified with the ICD‐9 diagnosis code‐based approach) to perform chart review of 54 randomly selected putative MGUS patients first identified based on a first serum M‐protein test result between 0 and 3 g/dL between 2008 and 2014 (“index” M‐protein test), with at least 1 year of health plan membership prior to the index M‐protein test result and with no subsequent diagnosis of MM or other lymphoid malignancy . We utilized the subset of these 54 health plan members who were confirmed by medical chart review to have clinically diagnosed MGUS as a separate patient sample in whom to estimate the sensitivity of the ICD‐9 code‐based algorithm. Specifically, we searched those patients' electronic records for an ICD‐9 diagnosis code for MGUS (273.1) before or within 1 year after the index M‐protein test. A more comprehensive evaluation of algorithm sensitivity was beyond the scope of this project.2.5As an exploratory exercise to assess the accuracy of the MGUS diagnosis made by physicians in the chart notes in comparison to current MGUS diagnostic criteria,2.6The distributions of demographic characteristics  and the Charlson comorbidity index were obtained for the subsample of 100 ICD‐9 algorithm‐identified potential cases randomly selected for chart review. We also utilized the chart review findings to calculate the PPV for this subsample to inform the probability that an MGUS patient identified by the electronic record ICD‐9 code‐based algorithm truly had a physician diagnosis of MGUS (the gold standard for case confirmation for this project). Specifically, among the subsample of ICD‐9 algorithm‐identified putative MGUS cases subjected to chart review, the PPV was calculated as:We calculated a second PPV among the further restricted subsample after applying the exclusion criterion based on a diagnosis of any lymphoid malignancy during the study period using the same formula as above. For that second PPV calculation, the additional exclusion criterion was applied to both the denominator and the numerator of the calculation. In the separate subset of putative MGUS cases first identified by the M‐protein test result‐based alternative algorithm (described above) and subsequently confirmed by medical chart review to have a clinician diagnosis of MGUS, we estimated the sensitivity of the ICD‐9 code‐based algorithm as:33.1A total of 8861 potential MGUS cases who met the eligibility criteria were identified using the case‐identification algorithm. Of these, we randomly selected 100 cases for chart review confirmation. Of these 100 potential cases, 58 were male, and 42 were of non‐Hispanic white race/ethnicity . The charts for the 42 cases with no M‐protein lab value contained comments indicating that the serum protein electrophoresis result was not quantifiable; however, other chart information indicated that these cases were, in fact, all confirmed by immunofixation and/or free light chain testing to be true MGUS cases.When we investigated the potential misclassification of smoldering MM as MGUS among the confirmed cases with no quantifiable M‐protein in the chart, we did not find any mention of a smoldering MM diagnosis within the chart review period. Of the full set of 90 confirmed MGUS cases, 3 developed MM within 2 years after the index ICD‐9 code date.3.3In the analyses to estimate the sensitivity of the ICD‐9‐based algorithm, 40 of the 54 potential MGUS cases initially identified by an eligible M‐protein test results were confirmed to be true clinically diagnosed MGUS cases by manual chart review. Of those 40 confirmed clinically diagnosed MGUS cases, 35 had an ICD‐9 diagnosis code before or within 1 year after the index M‐protein test, corresponding to an estimated sensitivity of 87.5%  and/or the lack of findings from a bone marrow study. The unavailability of those details in the medical charts prevented the hematologists from ruling out a more advanced diagnosis than MGUS, for example, smoldering MM or MM, for the “possible” cases. 4We confirmed an algorithmic approach that can be used to efficiently and accurately identify clinically diagnosed prevalent MGUS cases for population‐based research to study outcomes of MGUS and factors associated with progression to malignancy. Our results suggest that the diagnosis code‐based algorithm has excellent PPV and likely also satisfactory sensitivity for ascertaining individuals with clinically diagnosed MGUS.Our findings are aligned with results of a Danish study that used ICD diagnosis codes to identify patients with MGUS who were subsequently confirmed with chart reviews.More recently, an algorithm was developed to identify MGUS cases using electronic health records from a large, community‐based healthcare group.The hematologist adjudication findings suggested that MGUS diagnoses made in the community‐based practice may not always involve a complete symptom work‐up and/or bone marrow study within an applicable time window . Furthermore, other underlying conditions can contribute to the reporting of certain forms of MM‐defining end organ damage , yet the potential causes for the end organ damage are not always discussed in the chart. These practice patterns are likely also present in other community‐based practice settings. This finding suggests potential misclassification between MGUS and smoldering MM in real‐world practice, although the apparently missing clinical workups may have been completed at a time outside of the chart review window utilized for this study. We attempted to assess the magnitude of this potential misclassification by searching for MM diagnoses within 2 years after the index date. Of the 90 confirmed MGUS cases, only 3 developed MM within 2 years. This observation suggests that the potential misclassification of smoldering MM as MGUS by our ICD‐9‐based algorithm is small in magnitude given that the progression rate to MM for smoldering MM is expected to be much higher, for example, 10% per year for the first 5 years after diagnosis, whereas that for MGUS is ~1% per year.There are several other limitations to consider when interpreting our results. First, this study was not designed to assess the specificity or negative predictive value of our algorithms because of the focus on the reliable identification of individuals with a physician diagnosis of MGUS for inclusion in studies of outcomes of MGUS. For that purpose, the PPV and sensitivity were the most relevant parameters to evaluate. Second, we could not distinguish newly made MGUS diagnoses from those previously known due to insufficient documentation about the timing of a first MGUS diagnosis in the chart notes. Of note, since MGUS is an asymptomatic condition, the exact timing of MGUS onset cannot be determined for any patient in usual clinical care. A strength of our approach is that it allows the identification of a large proportion  of clinically diagnosed MGUS patients at any given point in time. As an additional limitation, we note that our study period ended prior to the transition from ICD‐9 to ICD‐10 code use, which occurred in 2015. Potential differences in relevant code(s) in the ICD‐10 system should be considered when applying the ICD‐based algorithm to more recent years, as should the incorporation (around 2014) of serum free light chain testing into standard clinical workups to diagnose MGUS.Although we designed this study to validate ascertainment of clinically diagnosed MGUS, it should be noted that undiagnosed MGUS is prevalent in older populations; indeed, approximately 80% of prevalent MGUS cases are unrecognized.Despite some limitations, our findings may be useful for certain types of epidemiologic studies, such as to investigate risk factors for MGUS malignant progression or to improve clinical surveillance for more serious non‐malignant outcomes. Such studies could accelerate identification of prevention strategies for more severe MGUS outcomes that would be considered clinically actionable, including MM and lymphoproliferative disorders. Results from the latter could be particularly useful for justifying larger screening‐based studies to develop risk‐prediction models among individuals with MGUS.Hilary C Tanenbaum: Data curation (lead); formal analysis (lead); investigation (lead); project administration ; validation ; writing – original draft . Brenda M Birmann: Conceptualization ; funding acquisition ; methodology ; writing – review and editing (lead). Kimberly Bertrand: Methodology (supporting); writing – review and editing (supporting). Lauren Teras: Methodology (supporting); writing – review and editing (supporting). Amrita Y Krishnan: Methodology (supporting); writing – review and editing (supporting). Hoda Pourhassan: Investigation (supporting); writing – review and editing (supporting). Scott Goldsmith: Investigation ; writing – review and editing . Kim Cannavale: Investigation (supporting); project administration ; validation ; writing – review and editing (supporting). Sophia S Wang: Conceptualization ; funding acquisition ; methodology (supporting); writing – review and editing (supporting). Chun Chao: Conceptualization ; methodology ; supervision (lead); writing – original draft .The authors have stated explicitly that there are no conflicts of interest in connection with this article.This study is approved by Kaiser Permanente Southern California IRB, Approval # 11139.


Managing ecosystems to effectively preserve function and services requires reliable tools that can infer changes in the stability and dynamics of a system. Conceptually, functional diversity (FD) appears as a sensitive and viable monitoring metric stemming from suggestions that FD is a universally important measure of biodiversity and has a mechanistic influence on ecological processes. It is however unclear whether changes in FD consistently occur prior to state responses or vice versa, with no current work on the temporal relationship between FD and state to support a transition towards trait‐based indicators. There is consequently a knowledge gap regarding when functioning changes relative to biodiversity change and where FD change falls in that sequence. We therefore examine the lagged relationship between planktonic FD and abundance‐based metrics of system state (e.g. biomass) across five highly monitored lake communities using both correlation and cutting edge non‐linear empirical dynamic modelling approaches. Overall, phytoplankton and zooplankton FD display synchrony with lake state but each lake is idiosyncratic in the strength of relationship. It is therefore unlikely that changes in plankton FD are identifiable before changes in more easily collected abundance metrics. These results highlight the power of empirical dynamic modelling in disentangling time lagged relationships in complex multivariate ecosystems, but suggest that FD cannot be generically viable as an early indicator. Individual lakes therefore require consideration of their specific context and any interpretation of FD across systems requires caution. However, FD still retains value as an alternative state measure or a trait representation of biodiversity when considered at the system level. Using species‐level plankton trait and abundance data from five highly monitored lakes, we determined the timing of functional diversity change relative to ecosystem state/functioning. Simple cross‐correlation and novel convergent cross mapping techniques revealed that planktonic functional diversity was weakly associated with state , but that both measures changed simultaneously. This implies functional diversity is not a leading indicator of state change but contains additional information absent in the state measures used here. Ecosystem state or functioning is considered the critical target in this regard as its disruption can result in the loss of many ecosystem services upon which human societies are dependent  is a collection of phenotypic traits that determines their temporal and spatial impacts on their surroundings and each other  was compiled from five long‐term freshwater lake datasets curated by a range of government, university and not‐for‐profit sources: Lake Kasumigaura , functional dispersion (FDis) and functional evenness (FEve)—see Supplementary Information and Figure mFD’ package , and the observed Pearson correlation coefficient compared to a distribution of pseudorandom correlation coefficients. These coefficients were generated via permutation, where 10,000 surrogate functional diversity time series were constructed from a red/autocorrelated noise process informed by the observed data:To limit the likelihood of spurious correlation, both the raw time series and permutations were made stationary prior to cross correlation by linear detrending. We then accounted for seasonality by additively decomposing the seasonal component of the original time series  and subtracting this estimate from the model residuals  across lags were then compared to the permuted 2.5% and 97.5% quartiles to discriminate a stronger cross correlation than expected by serial dependence, and at which lags that may occur. If lags are negative and transgress these ‘confidence intervals’, functional diversity change occurs prior to changes in system state, whereas if lags are positive then functional diversity lags state change. Conversely, if the observed correlation resides within the 2.5% and 97.5% quartiles, then we consider functional diversity to not correlate significantly with system state.2.4rEDM’ package  changed prior to changes in Community, Density and trophic ratio (Z_P.ratio), while the multivariate index of variability (MVI) displayed additional higher frequency fluctuations not identifiable in the other metrics. Functional diversity metrics also displayed unique trends depending on both the system and guild (phytoplankton or zooplankton), for example phytoplankton functional evenness (phyFEve) in Lake Kasumigaura displayed abrupt changes compared to other lakes, despite phytoplankton functional dispersion (phyFDis) being similar across lakes  and cross‐correlations (i.e. when one time series is lagged relative to the other). A strong instantaneous correlation would imply the functional dimension of biodiversity is related to state/functioning, whereas a strong cross‐correlation at a negative lag would suggests that functional diversity leads changes in state. However, we found correlations were inconsistent across all five of our lake systems Figure , with eaWhen we considered lagged cross‐correlations (LagX), most relationships increased in average absolute correlation coefficient Table , but onl3.3When causal relationships were estimated using CCM, many of the observed weak cross‐correlations at Lag0 display causal forcing, although the more nuanced approach indicates that many of the previously identified correlations Figure  may be sInterestingly, introducing lags improved the strength of causality by an average of 0.18 skill , yet did not increase the proportion of causal cross mappings Figure . With laFigure 4phyFDis) was universally related with total planktonic density (Density) albeit synchronously. Conversely, bi‐directional causality was relatively prevalent between functional diversity and state when the complex lagged relationship is disentangled using CCM, although Fisher Information (FI) often led functional diversity. In both approaches, individual lakes expressed unique association strengths which limits our ability to make general conclusions on the use of functional diversity as a warning of ecosystem change. Functional diversity appears not to change consistently prior to abundance‐based system state metrics overall and so is impractical for use by managers as a pre‐emptive indicator of state change. It does however display unique dynamics distinct from state that may indicate their use as an alternative measure rather than a leading indicator.Here, we provide the first insights into how planktonic functional diversity estimated from literature average trait values temporally change relative to abundance‐based metrics of system state. Previous work has shown that functional diversity is related to system functioning, but we go beyond this by highlighting how considering the sequence of phenomenological signals is critical to understanding which dimensions of biodiversity are most sensitive to change. We find that simple correlative techniques described no or very weak synchronous relationships between functional diversity and state, an unexpected finding which is not substantially improved when lags between time series are considered. However, phytoplankton functional dispersion .Similarly, the absence of strong functional diversity–state relationships was unexpected considering the bulk of literature reconciling ecosystem state with the taxonomic and functional dimensions of biodiversity, both in planktonic  than the short (Lake Mendota and Windermere). While this provides more data points for both correlation and CCM, our conservative approach of detrending and referencing an autocorrelated, permuted null distribution mitigates the likelihood of spurious correlations resulting from the shared system and larger datasets. As a result, we believe our results are valid.The ability of functional diversity to pre‐empt system change may also be hampered by the quality of estimates from literature average values. Hutchinson's paradox   to ecosystem managers.6All authors declare no conflict of interest.Data S1Click here for additional data file.


With support from PEPFAR, millions of lives have been saved, including 5.5 million children born HIV‐free . FurtherThis World AIDS Day, we look ahead with optimism to a future where HIV is no longer a public health threat, and every country leads an HIV response that is person‐centred to meet the overall health and wellbeing of its population. Here, we outline three essential priorities for sustaining the HIV/AIDS response, as outlined in PEPFAR's recent five‐year strategy : transfoFrom the outset of the global HIV epidemic, it was clear that the HIV/AIDS response required a political commitment to ensure an equitable and whole‐of‐government response. Success stories from countries like Botswana have shown that a sustainable response can be achieved through evidence‐based prevention and treatment strategies supported by non‐discriminatory laws that address stigma and promote equity . Ending To secure the long‐term sustainability of HIV response efforts, it is imperative that all countries fulfil their healthcare funding commitments; sustained domestic investments, which already finance most of the health spending in low‐ and middle‐income countries, are essential regardless of their gross national income . This coAs countries reach and sustain the 95‐95‐95 targets, domestic resources must be the cornerstone of HIV financing. Economic growth offers an opportunity for many countries to increase their investment in health , competiThe rapid scale‐up of the HIV response over the past two decades has been mainly achieved with stand‐alone HIV care and treatment programmes . As counPEPFAR has a track record of using science and data to drive programming decisions over the last two decades. By adopting evidence‐based algorithms for HIV testing, prevention and treatment, using standardized laboratory tests and streamlined data monitoring systems, under‐resourced health systems were able to provide care and save more than 25 million lives . To realUltimately, the path to securing and sustaining the UNAIDS 95‐95‐95 targets requires transformative political leadership, sustained financial commitment and programmatic innovation. In all countries, prioritized and sustained efforts are necessary to realize these targets and ensure that no one is left behind. PEPFAR remains committed to supporting partner countries on this journey, working towards a future where each nation leads its HIV response, with PEPFAR's support when necessary.Ambassador Dr. John Nkengasong currently serves as Global AIDS Coordinator and Senior Bureau Official in the Bureau of Global Health Security and Diplomacy.The first draft was prepared by MJAR. All subsequent drafts were reviewed and revised by all other authors.The study was supported by the US Government.The authors report no competing interests.