Amyloidosis is a heterogeneous disease characterized by tissue deposition of abnormally folded fibrillary proteins that can manifest itself by a wide variety of symptoms depending on the affected organs. GI involvement among amyloidosis patients is common. Its clinical manifestation often presents with nonspecific symptoms such as weight loss, diarrhea, and malabsorption. With no specific treatment existing for GI amyloidosis, therapy focuses on impeding amyloid deposition and managing the patients' symptoms with supportive measures. Here, we present an AL‐amyloidosis patient with GI involvement and intestinal failure (IF) who was successfully treated with the glucagon‐like peptide‐2 (GLP‐2) analogue teduglutide. Over the course of treatment with teduglutide, the patient was able to achieve independence from parenteral nutrition and experienced a significant improvement in quality of life (QoL) as stool frequency and consistency improved, urinary output was stabilized and body weight as well as body composition improved over the course of teduglutide therapy. With no longer being exposed to the burden and associated risks of parenteral nutrition, we were able to reduce the potential morbidity and mortality rate as well as to improve the patient's overall QoL. Intestinal tissue biopsy workup revealed a histopathological correlate for the clinical response; Congo‐Red‐positive intestinal depositions almost completely disappeared within 6 months of teduglutide therapy. Implementing intestinotrophic GLP‐2 analogue teduglutide may enrich the spectrum of treatment options for amyloidosis patients with IF who are dependent on parenteral support. Graphical Abstract The patient was first presented to our hospital after the initial diagnosis of renal AL‐amyloidosis of the kidneys was made and transferred with suspicion of GI involvement.2) prompted a kidney biopsy with the histopathologic workup clearly revealing an AL‐amyloidosis with glomerular deposition of lambda light chains. After having already lost 10 kg within 6 months, the patient was introduced to our clinical department of hematology and hemostaseology and treated interdisciplinary with our IF unit .The underlying plasma cell dyscrasia was treated with the monoclonal antibody daratumumab and the proteasome inhibitor bortezomib: The patient received an induction therapy consisting of three cycles of daratumumab and dexamethasone and nine cycles of daratumumab, bortezomib and dexamethasone followed by a maintenance therapy of daratumumab and dexamethasone. With that treatment, the patient revealed a good hematologic response . Nevertheless, in terms of organ therapy response, we observed a disease progression: although an improvement of the protein/creatinine ratio and albumin/creatinine ratio with 4459 and 3380 mg/g, respectively, could be achieved, renal function deteriorated with an over 25% increase of serum creatinine after nine cycles of therapy  and intravenous fluids with additional water‐soluble and fat‐soluble vitamins, trace elements, and albumin (20 g) on a daily basis  and sepsis, the option of off‐label treatment with teduglutide was discussed within an interdisciplinary team. The possibility of achieving enteral autonomy through teduglutide therapy and adjusting him to an optimal diet without the disadvantages of PS was presented to the patient who agreed to a therapy attempt with teduglutide.At the beginning of the treatment, the patient received an adjusted dose of teduglutide due to his renal function impairment. Nevertheless, the patient showed an excellent response and tolerance to teduglutide so that the dose could be increased to the full, body weight‐adjusted dose with improvement of the renal function after 3 months.Throughout treatment with teduglutide, the patient's dependency on PN was eliminated  was poor. With decreasing physical strength and malnourishment and a significant body weight loss, PS was an unavoidable measure in the course of treatment leading to a stabilization of the health status. However, with PS it was impossible to sufficiently improve the patients' symptoms and enable a significant body weight gain. Furthermore, due to PS the patient was now also exposed to new risks such as CLABSI, central thrombosis, and IF‐associated liver disease.The synopsis of the clinical findings led to the experimental approach of treating the patient with the intestinotrophic growth factor teduglutide, which is currently approved and specifically indicated for the treatment of SBS patients with IF (SBS‐IF).Another interesting finding of this case report is the histopathological workup of the intestinal biopsies revealing a potential explanation for the excellent clinical outcome. The patient received a colonoscopy at the initial presentation at our institution where the pathological workup in terms of a positive Congo‐Red staining of the biopsy specimens confirmed the diagnosis of intestinal involvement of the AL‐amyloidosis. After 6 months of teduglutide treatment with an excellent clinical response to the teduglutide therapy, another colonoscopy with intestinal biopsies was performed. Histopathological analysis revealed a near total disappearance of the Congo‐Red positive stained material with only remnant positive staining in single fibers of the lamina propria of the small bowel and a complete disappearance in the large bowel. As the Congo‐Red staining is highly specific for the amyloid deposits, this would mean intestinal regeneration from the amyloidosis.Nevertheless, an explanation for the observed phenomena is yet to be awaited and needs further research. The intestinal amyloid deposits are usually observed in the stromal compartment and subsequently hinder intestinal function, while current knowledge of the functional principle of the GLP‐2/GLP‐2R axis involves the mucosal crypt‐villus axis as activation induces crypt cell proliferation and exerts anti‐apoptotic actions of the enterocytes at the tip of the villi.4This case report describes a new treatment approach of an amyloidosis patient with IF who was successfully treated with the GLP‐2 analogue teduglutide. The treat‐to‐target goal of enteral autonomy in such patients seems to be of utmost importance as it eases the patients of PS‐associated morbidity and mortality while enabling improved body weight and composition as well as QoL.Clara Luhn: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; validation; visualization; writing – review and editing. Hermine Agis: Conceptualization; formal analysis; methodology; validation; writing – review and editing. Elisabeth Hütterer: Conceptualization; methodology; validation; writing – review and editing. Ingrid Simonitsch‐Klupp: Conceptualization; validation; writing – review and editing. Christopher Dawoud: Conceptualization; validation; writing – review and editing. Anton Stift: Conceptualization; validation; writing – review and editing. Felix Harpain: Conceptualization; data curation; formal analysis; methodology; project administration; resources; supervision; visualization; writing – review and editing.None.Felix Harpain reports a grant and lecture fee from Takeda, outside the submitted work. Elisabeth Hütterer and Anton Stift report lecture fees from Takeda, outside the submitted work. Clara Luhn, Hermine Agis, Ingrid Simonitsch‐Klupp, and Christopher Dawoud have indicated they have no conflict of interests to disclose.Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.


Acer rubrum (red maple), Betula papyrifera (paper/white birch) and Abies balsamea  from the Acadian Phenocam Network as well as multiple growing season observations from the North American PhenoCam Network we parameterized eight leaf emergence and six leaf senescence models for each species which span a range in process and driver representation. With climate models from the Fifth Phase of the Coupled Model Intercomparison Project (CMIP5) we simulated future leaf emergence, senescence and season length (senescence minus emergence) for these species at sites within the Acadian Phenocam Network. Model performances were similar across models and leaf emergence model RMSE ranged from about 1 to 2 weeks across species and models, while leaf senescence model RMSE ranged from about 2 to 4 weeks. The simulations suggest that by the late 21st century, leaf senescence may become continuously delayed for boreal species like Betula papyrifera and Abies balsamea, though remain relatively stable for temperate species like Acer rubrum. In contrast, the projected advancement in leaf emergence was similar across boreal and temperate species. This has important implications for carbon uptake, nutrient resorption, ecology and ecotourism for the Acadian Forest Region. More work is needed to improve predictions of leaf phenology for the Acadian Forest Region, especially with respect to senescence. Phenocams have the potential to rapidly advance process‐based model development and predictions of leaf phenology in the context of climate change.The Acadian Forest Region is a temperate‐boreal transitional zone in eastern North America which provides a unique opportunity for understanding the potential effects of climate change on both forest types. Leaf phenology, the timing of leaf life cycle changes, is an important indicator of the biological effects of climate change, which can be observed with stationary timelapse cameras known as phenocams. Using four growing seasons of observations for the species  Acer rubrum) may diverge from boreal tree species in the Acadian Forest Region. Phenocams are powerful monitoring tools that aid in developing robust and widely applicable process‐based models of leaf phenology, allowing us to explore future patterns in leaf phenology.By the end of the 21st century under high emissions, leaf senescence and the length of the leafing period for temperate species such as red maple ( To optimize growing season length and reproduction potential while avoiding exposure of vulnerable tissues to adverse conditions, plants undergo annual changes that are timed relative to environmental cues such as temperature and daylength , Betula papyrifera (white/paper birch) and Abies balsamea  have contrasting geographic distributions in North America. Acer rubrum is a more temperate‐climate‐suited species that can be found growing as far south as Florida. Betula papyrifera and Abies balsamea are more boreal‐climate‐suited species that are relatively uncommon south of the midwestern US , Betula alleghaniensis (yellow birch) and B. papyrifera (white/paper birch) and conifer species like Abies balsamea  and Picea rubens (red spruce). These phenocams were operational throughout the 2019–2020 growing seasons, with several observation gaps in the autumn of 2019 and spring of 2020 due to camera malfunctioning. In the 2020 growing season, we replaced these cameras with cellular trail cameras. Overall, we observed leaf emergence over the 2019–2022 growing seasons and leaf senescence over the 2019–2021 growing seasons. The elevation for our sites ranges from 88 to 322 m above sea level, with most sites located below 200 m.To monitor the leaf phenology of Acadian tree species we installed phenocams at 12 sites in the Canadian province of Nova Scotia before the onset of the 2019 growing season Figure —had bothhttps://www.moultriefeeders.com/m‐50‐game‐camera). These cameras were then replaced with Spypoint Link‐Evo (https://www.spypoint.com/en/support/cellular‐trail‐camera/product‐link‐evo.html) cameras. Each camera was solar‐powered, north‐facing and mounted at the top of a 6‐m tower with a horizontal or else tilted ~5° downward landscape view, depending upon the local canopy situation. To ensure stability in the field of view, we used galvanized guy wire cables, aluminum angle tower leg braces and a fixed aluminum angle base. All images were retrieved either remotely using the Python selenium package  or relative greenness as is shown in Equation BG corresponds to the intensity (brightness) of the green colour channel, BR to the intensity of the red colour channel, and BB to the intensity of the blue colour channel. The GCC represents the intensity of the green colour channel versus the total intensity of all colour channels. We then filtered time series by three‐day moving window 50th percentiles of GCC values to remove both high and low outliers  comparison of curve‐estimated phenology to phenology obtained from daily (May) to weekly (June onwards) manual ground observations for three Populus tremuloides individuals at an external site in 2021, (4) comparison of curve‐estimated phenology for 15 individuals to the estimation of leaf phenology via visual inspection of images for 2019, 2020 and 2021 site‐years  at an external site. For both manual field and visual observations, we considered leaf emergence to occur when most leaves had emerged entirely from bud scales such that leaf midribs were visible and leaf senescence to occur when most leaves had begun to show autumn colouration. Curve‐estimated leaf emergence dates for the three Populus tremuloides individuals at the external site for the Spypoint Link‐Evo camera were equal to the reference manually observed date  and the Brinno camera estimate was 4 days early. Curve‐estimated leaf emergence values had a correlation of 0.78 with the 15 visual estimates, while curve‐estimated leaf senescence values had a correlation of 0.74. This performance was in line with previous studies which have shown correlation values of 0.52–0.99 for leaf emergence 0.61–0.99 for leaf senescence  fil2.2GCC is then calculated as shown in Equation GCC records from the PhenoCam V2.0 dataset, which includes observations up until the end of the 2018 growing season  accumulates forcing and chilling exposure without the stipulation that chilling requirements are to be met prior to the onset of forcing accumulation. Within the Alternating Model each day can contribute to either requirement until accumulated forcing has surpassed a critical threshold which is altered by chilling exposure, and leaf emergence occurs Basler, . The SeqAll leaf emergence models were applied using the phenor package in R with species‐specific training and validation for each available site‐year . We used 1 km × 1 km grids with the nearest central coordinates to each site location for each site‐year.To train each phenology model, we obtained daily weather data for each site‐year in both the Acadian and PhenoCam Network datasets up until 2021 from the Daymet: Daily Surface Weather Data on a 1‐km Grid for North America, Version 4 R1 dataset using the daymetr package in R . Each climate model output was downscaled and bias‐adjusted using the Bias Correction/Constructed Analogues with Quantile delta mapping reordering (BCCAQv2) method : RCP 2.6 (low emissions), RCP 4.5 (intermediate emissions) and RCP 8.5 (high emissions). We obtained simulated daily temperature data with the Coupled Model Intercomparison Project 5 (CMIP5) model ensemble of 24 climate models from ClimateData.ca . The more boreal‐typical species Betula papyrifera and Abies balsamea had reduced coverage of the growing season temperature ranges relative to Acer rubrum, though under similar temperatures tended to have similar or earlier timings of leaf emergence and senescence. Under similar temperatures, Abies balsamea in the Acadian Network tended to have a later leaf emergence in comparison to the PhenoCam Network. In contrast, leaf senescence had no clear linear relationship with late summer‐early autumn temperatures. While there is some overlap in leaf senescence timings for Abies balsamea in both networks, within the Acadian Network under similar conditions it tended to be earlier, prompting a reduced season length. Season lengths tended to increase with increasing mean annual temperatures across site‐years, though with values ranging on the order of weeks at a given annual average temperature within and among species. Overall, the Acadian Phenocam Network is situated with cold‐intermediate seasonal temperatures relative to the PhenoCam Network, though these species tend towards later leaf emergence and earlier leaf senescence, leading to a reduced season length.Leaf phenology patterns in relation to temperature were similar for the Acadian and PhenoCam Networks Figure . Within 3.2Acer rubrum  and Abies balsamea , though slightly beyond the range for Betula papyrifera . For Betula papyrifera 49% of the extension in season length is due to an earlier leaf emergence (18 days of 37‐day average). For Abies balsamea 51% of the extension in season length is due to an earlier leaf emergence (20 days of 40‐day average). On average, advances in leaf emergence under high emissions by the end of the 21st century were similar across species ranging from 16 to 22 days, while delays in leaf senescence vary from just 7 days for Acer rubrum to 19 and 20 days for Betula papyrifera and Abies balsamea, respectively.The projected change in the timing of leaf emergence, leaf senescence and the corresponding season length for the mid‐ and late‐21st century for each phenology model and emissions scenario is shown in Figure 4Betula papyrifera and Abies balsamea versus more temperate‐climate suited Acer rubrum due to a more pronounced leaf senescence delay. The species‐specific projections from our models agree with the findings of a 5‐year experimental study by Montgomery et al.  and senescence models . Model performances in our study indicate that the inclusion of additional drivers for leaf emergence and senescence could improve the realism of dynamic global vegetation models and predictions of vegetation growing season length.Despite the broad range of observations and training contexts in our study, all species and validations agree in that simple Thermal Time model is not optimal relative to other models which include additional drivers. The Thermal Time model is often used to simulate leaf phenology within Dynamic Global Vegetation Models that form the terrestrial vegetational component of Land Surface Models within Earth System Models  delay in leaf senescence by the end of this century with high emissions for Fagus sylvatica, Fu et al. , Betula papyrifera (paper/white birch) and Abies balsamea  across the Acadian Phenocam Network and accessed multiple growing season observations of these species from the North American PhenoCam Network. With these observations, we conducted species‐specific parameterizations of eight leaf emergence and six leaf senescence models which encompass a range in process and driver representation, resulting in 42 unique leaf phenology models. With these models, we simulated future patterns in leaf emergence, senescence and season length (senescence minus emergence) for these species at sites within the Acadian Phenocam Network based on projected weather from Climate Models within the Fifth Phase of the Coupled Model Intercomparison Project (CMIP5). All models performed similarly well, with model errors in the range observed by previous studies for both leaf emergence and senescence. Leaf emergence was better predicted by more complex models while leaf senescence was better predicted by relatively simple models. By the end of the 21st century with moderate or high emissions, leaf emergence will likely be 2 weeks earlier while the magnitude of leaf senescence change varies across species and models. Temperate species like Acer rubrum may have as little as a 1‐week delay in leaf senescence while leaf senescence for boreal species like Betula papyrifera and Abies balsamea may be 2 to 4 weeks later. Consequently, the length of growing season extension varies from about 3 weeks for Acer rubrum to more than 5 weeks for Betula papyrifera and Abies balsamea. This differential response pattern between boreal and temperate species in the Acadian Forest Region has important implications for forest ecology as well as biogeochemistry and forest‐based sectors of the economy . A promising avenue to enhance the confidence of leaf phenology predictions in the context of climate change is the improved monitoring and modelling of leaf senescence. Our work demonstrates phenocams have the potential to rapidly advance process‐based model development and, therefore, foster more confident predictions of leaf phenology.The Acadian Forest Region is a unique transitional zone composed of both boreal and temperate forest species in eastern North America. Leaf phenology, the timing of season leaf life cycle events, responds directly to climate change and thus serves as an important biological indicator. Stationary timelapse cameras, known as phenocams, are cost‐effective monitoring tools that can provide spatially and temporally replicated species‐specific observations of leaf phenology in a range of climatic contexts. We collected four growing seasons of observations for the species Lynsay Spafford: Conceptualization ; data curation (lead); formal analysis (lead); investigation (lead); methodology ; resources (supporting); software (lead); validation (lead); visualization (lead); writing – original draft (lead); writing – review and editing . Andrew MacDougall: Conceptualization ; data curation (supporting); formal analysis (supporting); funding acquisition (lead); investigation (supporting); methodology ; resources (lead); software (supporting); supervision (lead); validation (supporting); visualization (supporting); writing – original draft (supporting); writing – review and editing . James Steenberg: Conceptualization ; data curation (supporting); formal analysis (supporting); funding acquisition (supporting); investigation (supporting); methodology ; resources (supporting); software (supporting); validation (supporting); visualization (supporting); writing – original draft (supporting); writing – review and editing .


To assess whether pre‐operative focused cardiac ultrasound and lung ultrasound screening performed by a junior doctor can change diagnosis and clinical management of patients aged ≥65 years undergoing emergency, non‐cardiac surgery.This pilot prospective observational study included patients scheduled for emergency, non‐cardiac surgery. The treating team completed a diagnosis and management plan before and after focused cardiac and lung ultrasound, which was performed by a junior doctor. Changes to diagnosis and management after ultrasound were recorded. Ultrasound images were assessed for image and diagnostic interpretation by an independent expert.There was a total of 57 patients at age 77 ± 8 years. Cardiopulmonary pathology was suspected after clinical assessment in 28% vs. 72% after ultrasound . In 67% of patients, the perioperative management was changed. The changes were in fluid therapy in 30%, cardiology consultation in 7%, formal in‐ or out‐patient, transthoracic echocardiography in 11% and 30% respectively.The impact of pre‐operative focused cardiac and lung ultrasound on diagnosis and management of patients on the hospital ward before emergency non‐cardiac surgery by a junior doctor was comparable to previous studies of anaesthetists experienced in focused ultrasound. However, the ability to recognise when image quality is insufficient for diagnosis is an important consideration for novice sonographers.Focused cardiac and lung ultrasound examination by a junior doctor is feasible and may change preoperative diagnosis and management in patients of 65 years or older, admitted for emergency non‐cardiac surgery. We hypothesised that focused ultrasound examination performed by a junior doctor would alter patient diagnosis and management.In this prospective observational study, participants admitted to the Royal Melbourne Hospital were identified and screened for eligibility using the hospital's electronic emergency surgery booking database and eligible patients were assessed for inclusion by a junior researcher who was not responsible for the medical care of the patient. Inclusion criteria were patient aged 65 years or above and scheduled for emergency non‐cardiac surgery. Emergency surgery was defined as surgery required within 48 h and non‐elective admission. Exclusion criteria included results available for either resting or stress transthoracic echocardiogram, cardiac nuclear medicine scan or chest computed tomography performed within 12 months of screening. As this was a pilot study to determine the feasibility of junior doctor‐performed ultrasound on changes to diagnosis and management in the pre‐operative setting, a convenience sample size of 50 patients was selected to inform future sample size and provide preliminary evidence of efficacy.A standard assessment was performed by the treating surgical team comprising of clinical history, physical examination and standard investigations such as serum biochemistry, haematology, blood gas analysis, electrocardiogram and chest x‐ray. The treating surgical team was asked to complete a research form Appendix  detailinUltrasound was performed using a hand‐held ultrasound system, SonoSite iViz  with a phased array 1–5 MHz transducer, capable of colour flow Doppler and 2D measurements but not spectral Doppler. The focused cardiac and lung ultrasound examinations were conducted according to the iHeartScanet al.To determine haemodynamic state, the following components were assessed and reported: (i) Left ventricular volume, (ii) Left ventricular systolic function and (iii) Left atrial filling pressure based on interatrial septum movement.Identification of clinically significant valvular lesions was performed by observing leaflet appearance, and thickness and opening for stenotic lesions while regurgitant lesionsFor the lung ultrasound examination, the procedure was standardised and followed the iLungScan protocol as established by the University of Melbourne, Ultrasound Education Group.All images acquired during the study were stored on a secure cloud‐based server for assessment of image quality and interpretation by an independent expert (YY) qualified and experienced in focused cardiac and lung ultrasound and blinded to the patient's clinical information.The focused cardiac and lung ultrasound images recorded by the junior doctor (RV) were reviewed by this expert, and an interpretive report was completed for each patient. The report provided by the expert was not communicated to the treating surgical team and was used exclusively for assessment of image interpretation.Assessment of image interpretation for focused cardiac ultrasound was divided into (i) assessment of haemodynamic state and (ii) identification of clinically significant valvular lesions. The junior doctor's interpretation was considered accurate when all components were identical to the interpretation provided by the independent reviewer (YY). If images acquired by the junior doctor were of insufficient quality for the independent expert to comment on haemodynamic state or valvular dysfunction, the images were excluded from analysis.For assessment of lung ultrasound image interpretation, the expert interpreted as either presence or absence of collapse/consolidation, interstitial syndrome/acute pulmonary oedema, pneumothorax and/or pleural effusion as described above. For each pathology, the junior doctor's interpretation was considered accurate when identical to the interpretation provided by the independent observer.Image quality assessment was performed using a previously described image quality scoring systemThe primary outcome was any change in cardiac or respiratory diagnosis due to ultrasound examination performed by the junior doctor. Secondary outcomes assessed any changes in management plan due to ultrasound examination. Other secondary outcomes included quality of image acquisition and interpretation of focused cardiac and lung ultrasound performed by the junior doctor.Data on diagnosis and patient management are presented as percentages of patients, and data on image quality are presented as median image quality scores with interquartile range. To assess estimates of interobserver agreement between a junior doctor and an expert reviewer beyond that expected by chance, Cohen's Kappa (k) statistics was used. Values of k < 0.20 indicated poor strength of agreement, k = 0.21–0.4 fair strength of agreement, k = 0.41–0.60 moderate strength of agreement, k = 0.61–0.80 good strength of agreement and k = 0.81–1.0 very good strength of agreement. For this secondary outcome measure, p values<0.05 were considered statistically significant. Only images deemed of acceptable image quality by the expert reviewer were included. As this observational study was a pilot study, group comparisons were not performed. Descriptive data were stored in Microsoft Excel 2016 , and for statistical analyses, we used Stata/IC 15.1 for Mac .The Human Resources and Ethics Committee from the Royal Melbourne Hospital approved the study (LNR/16/MH/91), which conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Prior written informed consent was obtained from all participants between June 2017 and October 2018.In the period between June 2017 and October 2018, 83 patients were screened for eligibility, and 76 patients met the criteria of which 57 patients had complete datasets as displayed in Figure The impact of ultrasound performed by a junior doctor on diagnosis and management is summarised in Figure a‐priori minimum acceptable image quality score of 64%. The lowest image quality score was in the apical 4‐chamber view with median score of 6 (4–7) out of 9. The highest score was in the parasternal long axis view with a median of 8 (6–9) out of 10.Image quality scores for focused cardiac ultrasound are shown in Table Of the 57 patients enrolled in the study, Forty patients had saved imaging deemed of acceptable quality by the independent reviewer for assessment of haemodynamic state interpretation, whereas only 18 patients had imaging with acceptable quality for assessment of valvular interpretation. For lung ultrasound, 22 patients had imaging with acceptable quality for assessment of the interpretation of lung ultrasound findings .Interobserver agreements beyond chance, for assessment of the haemodynamic component, valvular component and lung component were assessed using Cohen's Kappa statistic. For the identification of clinically significant valvular disease (n = 18), Cohen's Kappa was 0.55 , and for the lung ultrasound component (n = 22), Cohen's Kappa was 0.83 . For the overall haemodynamic state (n = 43), Cohen's Kappa was 0.065 . A normal haemodynamic state identified by the expert sonographer was misinterpreted as abnormal by the junior doctor in 28/43 patients (65%), while only one patient with abnormal haemodynamic state was missed.In this observational study, we showed that focused cardiac and lung ultrasound examination performed by a junior doctor on patients presenting for emergency non‐cardiac surgery resulted in frequent changes in diagnoses and management compared with standard pre‐operative clinical assessment. When clinically important abnormalities were diagnosed on ultrasound, the predominant effects were adjustments in fluid administration, involvement of other inpatient units in the perioperative optimisation of patients and ordering of either chest x‐ray or conventional transthoracic echocardiography.et al.A number of studies have previously described a high impact of pre‐operative ultrasound on cardiac and lung ultrasound diagnosesThe mean image quality score in this study was above the acceptable lower limit of 64%.et al.A large proportion of patients had imaging of insufficient quality for assessment of valvular disease, and two cases of clinically important aortic stenosis were missed by the junior doctor performing the ultrasound. The correct diagnosis using ultrasound requires both image acquisition and image interpretation, both of which are operator dependent. Compared with an expert sonographer using a high‐end cart‐based ultrasound machine performing comprehensive ultrasound examination, it is expected that junior doctors using hand‐carried ultrasound devices will miss important pathology. This was demonstrated by Kobal For assessment of haemodynamic state, we demonstrated poor strength of agreement between the junior doctor and the expert's interpretation. The majority of poor agreement was due to misinterpretation of normal haemodynamic state as abnormal by the junior doctor. The reasons for this are unclear but might reveal a junior doctor's tendency to over‐diagnose when there is uncertainty, especially when faced with borderline cases or cases with inadequate imaging quality.Our study identified a delay in surgery in seven patients following ultrasound examination. In all seven patients, this delay was the result of awaiting pre‐operative formal TTE or consultations by other inpatient units. However, ultrasound in this study uncovered a large proportion of patients with potentially serious cardiac pathology and the inconvenience or expense in generation of extra formal TTEs and surgical delay may be acceptable if it improves patient outcomes. While this was not investigated in our study, this likely warrants further research in the future. Furthermore, all ultrasound examinations in this study were performed by a single sonographer from the research team, and therefore, the timing of the ultrasound is limited by the sonographer's availability. However, if junior doctors were more widely trained in point‐of‐care ultrasound then it could be performed on admission by the admitting surgical team as part of routine assessment allowing for more time for definitive investigations and consultations with relevant inpatients units where necessary.via a written report, and while the sonographer was requested not to offer management advice, verbal discussion of the findings was not precluded.The current study is limited by its observational design, and its inability to assess whether changes to diagnosis and management improves patient outcomes. Nevertheless, the goal of this study was mainly to establish a proof of concept. Secondly, in this study we assessed the quality of junior doctor‐performed image interpretation based on the stored images and the large number of excluded studies due to poor image quality limits our ability to draw meaningful conclusions regarding accuracy. Therefore, it is important for a novice sonographer to recognise when image quality is too poor for diagnosis and we advise that a lead‐in phase of training and verification will be important for future trials investigating the utility of point‐of‐care ultrasound in clinical practice. Thirdly, larger‐scale studies are warranted to reproduce the findings reported in this study. Furthermore, our study is limited by the use of a single sonographer and a single expert reviewer and future studies could benefit from more than just one junior doctor and one expert to serve as comparators. Lastly, the primary method of communicating the ultrasound results to the treating team was A focused cardiac and lung ultrasound examination performed by a junior doctor on patients presenting for emergency non‐cardiac surgery can change pre‐operative diagnosis and management. The predominant effects of detecting abnormalities on ultrasound were changes in fluid therapy, involvement of other inpatient units in the perioperative optimisation of patients and ordering of imaging to confirm ultrasound findings.We acknowledge that the authorship listing conforms with the journal's authorship policy and that all authors are in agreement with the content of the submitted manuscript.No funding information is provided.None to declare.Appendix S1. Diagnosis and management form.Click here for additional data file.Appendix S2. Image quality scoring system.Click here for additional data file.Appendix S3. Background paper on image quality scoring system.Click here for additional data file.Table S1. Ultrasound training of the junior doctor performing focused ultrasound.Click here for additional data file.Table S2. Preoperative clinical diagnoses, ultrasound findings and management changes in patients that had significant findings on point‐of‐care ultrasound.Click here for additional data file.Figure S1. Ultrasound report form.Click here for additional data file.Figure S2. Study process.Click here for additional data file.


Interventions distributing micronutrient powders (MNPs) and small‐quantity lipid‐based nutrient supplements (SQ‐LNS), or home fortification products (HFPs), have the potential to improve infant and young child feeding (IYCF) practices and children's nutrition. We systematically searched for studies on the effect of interventions distributing HFP on IYCF practices. We identified 12  studies: seven programmes with IYCF behaviour change communications (BCC) and MNP (IYCF‐MNP) and one provided MNP without IYCF BCC (MNP only). Three SQ‐LNS studies came from randomised trials without an IYCF component (SQ‐LNS only) and one from a programme with both IYCF BCC and SfQ‐LNS (IYCF‐SQ‐LNS). Five IYCF‐MNP programmes reported positive associations with some IYCF practices—four with minimum dietary diversity, two with minimum meal frequency, four with minimum acceptable diet, and three with the initiation of complementary foods at 6 months. Two reported no association between MNP and IYCF indicators, and one reported a decline in IYCF practices during the intervention, although it also reported significant changes to the IYCF programme during the evaluation period. Two studies from interventions that distributed SQ‐LNS  reported a positive association with IYCF practices; one trial reported no change in breast milk intake with the provision of SQ‐LNS and one found no association with IYCF practices. SQ‐LNS and MNP can address nutrient gaps for young children in low‐resource settings; our findings indicate that programmes that combine HFP with IYCF interventions may also contribute to improved IYCF practices in some settings. We systematically searched for studies on the effect of interventions distributing home fortification products (HFPs) on infant and young child feeding (IYCF) practices and identified 12  studies. Some interventions found an association with improved IYCF practices, and most of the interventions with significant associations were integrated programmes that included the distribution of HFP with a new, intensive IYCF behaviour change strategy that included frequent interpersonal counselling. We identified 12 studies distributing home fortification products (HFP) that assessed infant & young child feeding (IYCF) outcomes; few used experimental or quasi‐experimental study designs.Interventions associated with improved IYCF practices were predominantly programs that integrated HFP with a new, intensive IYCF behavior change strategy.HFP can fill nutrient gaps for infants and children in low‐resource settings; programs that combine HFP with IYCF interventions may also contribute to improved IYCF practices in some settings. AORadjusted odds ratioAPRadjusted prevalence ratioiLiNSinternational lipid‐based nutrient supplementsISSSFintroduction of solid, semisolid or soft foodsIYCFinfant and young child feedingMADminimum acceptable dietMDDminimum dietary diversityMMFminimum meal frequencyMNPmicronutrient powdersRCTrandomised controlled trialSQ‐LNSsmall‐quantity lipid‐based nutrient supplements1Malnutrition during early life increases the risk of mortality and morbidity in children and has lifelong consequences for physical and cognitive development  is an approach to improving the nutrient intake of young children and other nutritionally vulnerable groups which involves the addition of micronutrient powders (MNPs) or other specialised fortified products, such as lipid‐based nutrient supplements (LNS), to foods immediately before consumption   is defined as the percentage of infants 6–8 months of age who consumed solid, semisolid or soft foods during the previous day. However, given the varying study designs , some studies provided different indicators for reporting on the age at the introduction of solid foods. Two studies reported the WHO indicator for ISSSF in children 6–8 months , even though none of the trials were specifically designed to include an IYCF behaviour change communication (BCC) component . The iLiNS group did not find significant differences by the treatment group in the prevalence of children consuming the MDD, continued breastfeeding at 18 months or frequent breastfeeding (6 or more times per day) in any of the four trials, but they did report a reduced prevalence of infrequent consumption of animal source foods in the same two trials that found a significant difference in MMF.Of the three papers that reported on the WHO/UNICEF IYCF indicators, two were from clinical trials of home fortification with SQ‐LNS. One reported on IYCF practices in the WASH Benefits trial, an eight‐arm trial of water, sanitation, handwashing and nutrition interventions in rural Kenya . By contrast, there have been few programmes that have distributed SQ‐LNS, and thus all but one of the published studies are from randomised trials.Most of the studies from integrated IYCF‐MNP programmes found either no association with IYCF practices or a small beneficial effect on IYCF practices. One study, from Bangladesh, reported a decline in IYCF practices during the implementation of an integrated IYCF‐MNP programme, but important methodological limitations—namely the removal of CHW incentives for IYCF practices in the middle of the programme period—make it difficult to attribute the decline in IYCF practices to the use of home fortification products. From the studies available, it is not possible to isolate whether there is an independent effect on IYCF practices of adding home fortificants to existing, intensive IYCF. In most of the studies, the introduction of MNP was part of an integrated IYCF‐MNP programme, which included the introduction of a new, intensive IYCF BCC component  and improved IYCF practices  and selection of IYCF indicators, we were unable to perform quantitative summaries of the research on this topic.5Our findings indicate that programmes that combine home fortification products and IYCF interventions had positive and/or limited influences on IYCF practices. Given that that home fortification products contain several essential nutrients that are lacking in the diets of infants and young children in low‐resource settings, the integration of these products into national and subnational programmes has the potential to improve IYCF practices and nutrition outcomes in vulnerable children Figure .Lindsey M. Locks and Maria Elena D. Jefferds developed research questions and research methodology. Lindsey M. Locks and Katharine B. Newell screened abstracts and drafted the first draft of the manuscript. All authors contributed to the manuscript review including the addition of critical intellectual content. All authors read and approved the final version of the manuscript.The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centres for Disease Control and Prevention or UNICEF. The authors have no conflict of interest to declare.


Periodontal diseases (gingivitis and periodontitis) are frequently neglected, and yet represent the sixth most prevalent non‐communicable oral diseases affecting 796 million people worldwide according to the Global Burden of Disease study.In the current issue, Thomas et al. demonstrate that almost half of the pregnant women in their first trimester exhibited poor periodontal health, while those who developed periodontitis were more prone to develop gestational diabetes during their pregnancy.Importantly, up to one third of the pregnant women were unaware of their existing periodontal condition, as symptoms of gingival inflammation remained concealed. This seems to be a common pattern across the world as periodontitis is considered a “silent epidemic”, that may start and worsen with little or no pain. If left untreated, not only will periodontal diseases destroy the tooth supporting tissues, but they may further constitute a risk factor to several life‐threatening affections such as cardiovascular diseases, diabetes mellitus II, as well as to APOs. “Periodontal Health for a Better Life” has been emphasized by several health associations including the European Federation of Periodontology and World Health Organization among the few.Porphyromonas gingivalis and Prevotella melaninogenica.The progesterone and estrogen levels are known to peak during the second and third trimester of pregnancy, when one half of women with pre‐existing gingival inflammation are documented to exhibit significant exacerbation of bleeding in their gums in combination with changes in specific oral taxa, such as 2The reproductive age of a woman's lifetime, spans from menarche until menopause and is characterized by major changes in circulating hormone levels, frequently accompanied by a worsened oral health, altered saliva composition and considerable changes in structure (increased vascular permeability), cellular and humoral immune responses of the tooth supporting periodontal tissues (periodontium). Gingival tissues are indeed known to express estrogen‐specific receptors and hence to represent an estrogen‐sensitive tissue.Over 150 years, the gingival and periodontal inflammation observed in pregnant women were considered to be separate conditions from that of plaque‐induced gingivitis.3Periodontitis in the carrying mother has been associated with several APOs including the delivery of preterm and/or low birthweight babies, pre‐eclampsia, or gestational diabetes when all other cofounding risk factors have been taken into consideration Figure . HoweverP. gingivalis or Fusobacterium nucleatum have been retrieved from amniotic fluid samples collected in women with preterm labor and intact membranes. Nonetheless, whether the human fetus and the prenatal intrauterine environment are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. The most recent evidence does not support the presence of an “in‐utero microbiome” at term‐pregnancies.In the early 1990s, the biological plausibility of this association has been attributed to the microbial translocation into the peripheral bloodstream via disruption of the gingival epithelial barrier, and systemic trafficking of virulence factors during pregnancy to the intrauterine environment where they cause inflammatory and immune responses affecting the feto‐placental unit in experimental models.4One main oral health goal during pregnancy should be to avoid excessive dental plaque accumulation by enhancing oral hygiene and regular check‐ups with either an oral or prenatal healthcare professional. The achievement of an adequate periodontal health in pregnant women has in the past been hindered by myths surrounding the safety of dental/periodontal care during pregnancy. Thomas et al. reports that only 32.9% of the 407 pregnant women included in the larger obstetrical risk screening study were available for oral health screening and some dropped out due to dentist phobia. As far as their oral health was concerned, 41.3% had not been to the dentist at least one year prior to pregnancy. These findings are consistent with existing reports showing that there is low attendance to dental services among pregnant women due to a lack of oral health education, difficulties of access, along with dentist fear and concerns for the safety of the fetus. Specific dental plaque removal approaches together with professional oral health interventions, have been shown to be safe when implemented during the second trimester of pregnancy and efficient both in reducing gingival inflammation and enabling periodontal health to be maintained during pregnancy.


Parasite species that use two or more host species during their life cycle depend on successful transmission between these species. These successive host species may have different habitat requirements. For example, one host species may be aquatic while the other is terrestrial. To overcome this complicating factor in transmission, a wide diversity of parasite species have adaptations that alter the habitat preference in one host species to facilitate transmission to the next host species.Atriophallophorus winterbourni and Notocotylus spp., both have a life cycle with two host species. The aquatic snail Potamopyrgus antipodarum is the intermediate host, from which the parasites require transmission to dabbling ducks or other waterfowl. Of these parasites, A. winterbourni is most frequently found in snails from the shallow‐water margin. This may indicate parasite‐induced movement of infected snails into the foraging habitat of dabbling ducks.Two common trematode parasites in New Zealand, A. winterbourni were retrieved from the shallowest end of the cages, while Notocotylus spp. frequencies did not vary with depth.To test whether the parasites manipulate the snails to move into shallow water, we stretched tubular mesh cages across depth‐specific ecological habitat zones in a lake. Both infected and healthy snails were released into the cages. After 11 days, significantly higher infection frequencies of A. winterbourni induces its snail host to move into the shallow‐water habitat cannot be rejected based on the experimental results. Although further research is needed to address alternative explanations, the depth preference of infected snails may be due to a parasite adaptation that facilitates trophic transmission of parasites to dabbling ducks.The hypothesis that  Potamopyrgus antipodarum by the parasite Atriophallophorus winterbourni: infected snails seem to prefer the shallowest habitat. We were interested in movement across littoral habitat zones, and in order to test this, we designed cages that span a depth gradient in the lake. This allows for the investigation of movement patterns of snails in as natural a setting as possible.We provide evidence for behavioral manipulation of the snail  Parasites with complex life cycles require transmission between two or more host species to complete a full life cycle  and Notocotylus spp.  while A. winterbourni was associated with either dabbling ducks or diving ducks. However, the sample sizes in this study were relatively small  to draw conclusions about associations between definitive hosts and parasites.The New Zealand trematodes . Figure  both use Bisset, . Both pa Bisset,  found thA. winterbourni . After sufficient time passed for the snails to disperse within the cages, we assessed how infection frequencies with A. winterbourni and Notocotylus spp. varied with depth. While the frequency of infections by Notocotylus spp. was the same for all cage sections, we found that snails infected by A. winterbourni were most common in the shallowest part of each cage. This finding suggests that the snails' habitat choice along a depth cline is affected by A. winterbourni and that infected snails move across littoral habitat zones toward the shallow‐water margin.To test the hypothesis that 22.1Lake Alexandrina is a sub‐alpine lake that lies east of the Southern Alps in New Zealand. The habitat zonation in the lake is dependent on wave action and depth (light penetration), while the local width of each habitat zone depends on the steepness of the lake bed  cage in the water at the experimental site. After the experiment was terminated, 100 randomly selected snails were dissected from each of these two controls.In order to obtain a sample of snails with a high prevalence of infection, snails were collected on the 19th of January from the shallow‐water margins at two sites . Infection status by both A. winterbourni and Notocotylus spp. was recorded to estimate parasite prevalence in each sample. Juvenile snails smaller than 2.5 mm were not included. The period from the beginning of the experiment (January 20–February 17) until the end of the experiment was short enough to exclude exposure during the experiment as a significant factor, since infections take several months to develop , where randomly selected snails were dissected from the shallow, middle, and deep sections of each of the nine remaining cages between the 12th and 17th of February  was calculated using the R package car 3.0‐11  1‐m section of the cages  and in the deepest 1‐m section . The prevalence of A. winterbourni infections was not affected by either the turning treatment or the interaction term between the turning treatment and depth (Table A. winterbourni infections that were not at transmission stage (N = 4), were only found in the deepest cage section. There was no significant difference in the prevalence of snails infected by Notocotylus spp. between any of the depth‐specific cage sections . Further experiments could be performed with experimentally exposed snails from different habitats to clearly distinguish cause and effect, or by caging snails at various depths to test for habitat‐specific risk of infection. Thirdly, infected snails may have an increased foraging need due to energetic demands of the parasite. This could lead them to prefer biofilms in the shallow habitat, but we found no effect on cage turning. However, it should be noted that the algal growth during the experimental phase may have reduced the effect of the initial incubation phase of the cages. Furthermore, if an increased need for foraging was driving the aggregation in the shallow, the same would be expected for snails that are infected by Notocotylus spp., since these snails are more susceptible to starvation than those infected by A. winterbourni  while the—so far undescribed—Atriophallophorus sp. was more frequent than A. winterbourni in deeper habitat zones ; data curation (lead); formal analysis (lead); investigation (lead); methodology (lead); visualization (lead); writing – original draft (lead); writing – review and editing (lead). Claudia Buser: Methodology (supporting); writing – review and editing (supporting). Kirsten Klappert: Methodology (supporting); writing – review and editing (supporting). Jukka Jokela: Formal analysis (supporting); funding acquisition (lead); methodology ; supervision (supporting); writing – review and editing (supporting).This project was funded by the Swiss National Science Foundation grant 31003A_166667/1 and ETH Grant ETH‐36 15‐2, both awarded to JJ.The authors declare no competing interests.https://doi.org/10.5061/dryad.bzkh189f6].This article has earned an Open Data badge for making publicly available the digitally‐shareable data necessary to reproduce the reported results. The data is available at [


Forests contribute to numerous ecosystem functions and services and contain a large proportion of terrestrial biodiversity, but they are being negatively impaced by anthropogenic activities. Forests that have never been clear‐cut and have old growth characteristics, termed “near‐natural,” often harbor different and richer species assemblages than managed forests. Alternative management strategies may be able to balance the needs of biodiversity with the demands of forestry, but evaluation efforts are limited by the challenges of measuring biodiversity. Species richness is frequently used as a simple measure of biodiversity, but research indicates that it may not adequately capture community‐level changes. Alternatively, trait‐based measures of biodiversity may prove to be useful, but research is lacking. In this paper, we use a large dataset that includes 339 obligate saproxylic beetle species collected over a decade in the boreal region throughout southern Norway to: (1) establish if there is a difference in beetle community composition between near‐natural and managed forests; and (2) determine which measures of beetle biodiversity best indicate forest naturalness. We arranged the sites in an ordination space and tested for differences in community composition between these forest types. We also tested different measures of biodiversity to determine which were the most predictive of forest naturalness. We found a clear difference in community composition between near‐natural and managed forests. Additionally, three measures of biodiversity were most predictive of forest naturalness: proportional abundance of predators, community weighted mean (CWM) of wing length, and CWM of body roundness. The probability that a forest was near‐natural increased with the proportional abundance of predators but decreased with CWM wing length and body roundness. Although species richness was higher in near‐natural forests, the effect was not significant. Overall, our findings underscore the conservation value of near‐natural forests and highlight the potential of several measures of biodiversity for determining forest quality. There was a clear difference in saproxylic beetle community composition between near‐natural and managed forest, and three measures of saproxylic beetle biodiversity were most predictive of forest naturalness: proportional abundance of predators, CWM of wing length and CWM of body roundness. Although species richness was higher in near‐natural forest, the effect was not significant. Overall, our findings underscore the conservation value of near‐natural forests and highlight the potential of these measures of biodiversity for determining forest quality. ForestsBoreal forests represent the single largest pool of living biomass on Earth and span extensive areas across Earth's northern regions , with some deciduous tree species, and were classified as being either near‐natural or managed based on their management history, as in previous research . Lastly, only forests of mature age were included in the dataset, and all clear‐cuts were excluded because research indicates that clear‐cut sites are inherently different from sites with mature trees  or Eurasian aspen (Populus tremula), or were free hanging in the forests. Trap substrates  were roughly comparable between forest management categories (Table n = 38 sites). We controlled for this and other sources of introduced variation by including the sampling project as a random effect in our models . Sampling took place from May to August, and traps were emptied once a month during that time. All beetles collected at a single site were pooled for each year for the analysis. Beetles were identified to species level based on their morphology, following the taxonomy of the Norwegian Biodiversity Information Centre  as well as trait measures Table . Choosin2.1We first calculated several measures of biodiversity Table  for the p value and obtained a new critical threshold (α) of .003  ordination based on the Bray–Curtis dissimilarity matrix . Additionally, all the measures of biodiversity were significantly related to ordination axes . The mean species richness per year at near‐natural sites was 44 , whereas the mean species richness in managed forests was 30 . We found a clear difference in beetle taxonomic community composition between the forest types. The results from the PERMANOVA test indicated that there was a significant difference between the forest types after 999 permutations (p = .023) and decreasing beetle wing length . We also made two alternative models that predicted forest naturalness with body roundness and with species richness. These variables were excluded from the full model due to collinearity, but the ordination indicated that they may be important predictors of forest naturalness. Results from these models indicated that a forest is more likely to be near‐natural with decreasing body roundness of saproxylic beetles  and that a forest is more likely to be near‐natural with an increasing number of species, although this effect was not significant . When the AIC of the full, reduced, and two single‐covariate models were compared, the model including only body roundness was the lowest  trait is directly related to forest naturalness. It is important to point out that these are site‐level measures of functional diversity, and this does not mean that these traits are correlated for any single species. Instead, it indicates that e.g. sites with a high proportional abundance of predators or sites with a low mean value for wing length also tend to have species that are less round. Systematic differences in this body shape at the site level could have implications for how the community responds to environmental change since body shape influences species' cold and water loss tolerance ; data curation (lead); formal analysis (lead); investigation ; writing – original draft (lead). Tone Birkemoe: Conceptualization ; funding acquisition ; investigation ; methodology ; writing – original draft (supporting). Ryan C. Burner: Conceptualization (supporting); formal analysis (supporting); investigation ; writing – original draft (supporting). Anne Sverdrup‐Thygeson: Conceptualization ; funding acquisition ; investigation ; methodology (lead); writing – original draft (supporting).The authors have no conflict of interest to declare.Appendix S1Click here for additional data file.


Recent advances in multistable metamaterials reveal a link between structural configuration transition and Boolean logic, heralding a new generation of computationally capable intelligent materials. To enable higher‐level computation, existing computational frameworks require the integration of large‐scale networked logic gates, which places demanding requirements on the fabrication of materials counterparts and the propagation of signals. Inspired by cellular automata, a novel computational framework based on multistable origami metamaterials by incorporating reservoir computing is proposed, which can accomplish high‐level computation tasks without the need to construct a logic gate network. This approach thus eliminates the demanding requirements for the fabrication of materials and signal propagation when constructing large‐scale networks for high‐level computation in conventional mechanical logic. Using the multistable stacked Miura‐origami metamaterial as a validation platform, digit recognition is experimentally implemented by a single actuator. Moreover, complex tasks, such as handwriting recognition and 5‐bit memory tasks, are also shown to be feasible with the new computation framework. The research represents a significant advancement in developing a new generation of intelligent materials with advanced computational capabilities. With continued research and development, these materials can have a transformative impact on a wide range of fields, from computational science to material mechano‐intelligence technology and beyond. Inspired by cellular automata, an innovative approach by integrating reservoir computing into multistable origami metamaterials is proposed, enabling high‐level computations without conventional logic gate networks. Digit recognition and complex tasks are successfully implemented through experiments by a single actuator, revolutionizing the potential for intelligent materials in diverse applications from computational science to mechano‐intelligence. Today, a revolutionary idea of incorporating computing power into materials allows the integration of mechanical properties with information processing. While electronic and photonic computing are widely known, the field of mechanical material‐based computing is just in its early stages. This approach holds the natural advantage in terms of survivability in harsh environments and has the potential for various applications in the development of completely soft robots, distributed neuromorphic computing, and autonomous systems. By enabling materials to interact with their external environment and perceive and process information through autonomous shape morphing, intelligence emerges in mechanics. Many examples in nature, such as the Venus flytrap and mollusks, also provide evidence for the incorporation of computational capability into a physical body.Material properties such as shape reconfigurability,1 prog has been recognized as a tenable approach to achieving mechanical computing. The distinct stable configurations endow multistable metamaterials with nonvolatile mechanical memory. Moreover, the write, erase, and rewrite operations could be efficiently achieved by exploiting the snap‐through transitions among different stable configurations. By incorporating multiple cells and by tailoring the mechanical coupling between them, the transition sequences become customizable, thus enabling input‐output mapping similar to some basic logic gates. With more mechanical bits being integrated, complex calculations, such as full adders and logic circuits, have also been achieved. Particularly, higher‐level computing or programmable logic gates were explored but usually require scalable integrated circuits embedded into mechanical metamaterials. Note that the fundamental principle of mechanical computing follows the framework of modern electric computation, hence, high‐level computing operations can be implemented by integrating networked basic logic gates. Based on the one‐to‐one correspondence between the material components and electronic elements, high‐level mechanical computing will encounter bottlenecks due to the explosive growth in demand for material components and the strict requirements for signal propagation efficiency in materials.For engineering materials, abstracting mechanical bits from multistable structural configurations17 has discrete computing paradigms with Turing completeness, this paper proposes a novel computational framework based on multistable origami metamaterials to address the above‐mentioned bottlenecks in achieving high‐level mechanical computation. The framework, by treating the metamaterial as a mechanical network, not only inherits the merits of fast computation and nonvolatile memory from the snap‐through transitions of multistable metamaterials, but also features relatively low structural complexity and is less affected by the attenuation during signal propagation. With this, sophisticated high‐level learning tasks, such as handwriting recognition and long short‐term memory, can be performed in a benchmark multistable stacked Miura‐origami (SMO) metamaterial.Inspired by Cellular Automata (CA),21 disFigure ), while for the SMO metamaterial, state transitions can be induced by a variety of different actuation . Importantly, complex and discriminative transition behaviors are observed in both systems. Moreover, they can both be expanded in two or 3D space. As a result, the SMO metamaterial can be considered as a physical analogue of CA, and its computational potential could be unearthed in the context of CA‐based computation.The similarities between CA and SMO‐metamaterials are manifolds. The first thing to note is that they are both made up of a regular grid of cells, and each cell stays in one of a finite number of states. A typical CA cell is shown in Figure 27), w By integrating reservoir computing (RC), a specialized recurrent neural network with pre‐determined weights, into CA, artificial intelligence with learning capability would emerge. By feeding the input signal into a CA, rich transitions are generated in much higher dimensional state space by means of pre‐defined evolution rules; afterward, the entire dynamic response of the CA is used as a feature vector to be processed in the readout, as shown in the left panel of Figure The computational framework for CA and SMO‐metamaterials is similar. As discrete Turing universal models, CA have been used to simulate and predict a variety of industrial and biological processes.33 By 22.1 SMO prototypes are fabricated. Details of the fabrication process are described in Section 5. For a single bistable SMO cell, the experimental force‐displacement constitutive profile with two stable states is shown in Figure Based on the dual‐material 3D printing technique,40 SMOTo demonstrate the learning ability of SMO metamaterials, we first perform a classification task. The task is to recognize computer‐generated images of 5 × 4 pixels, see examples in the left panel of Figure The SMO metamaterial‐based computation includes three steps, namely, encoding, transition, and readout. In detail, the binary pixels of each row are first encoded into the SMO metamaterial to generate an initial stable configuration based on the above correspondence, see an example of the digit ‘3′ in Figure Another way to further highlight the significance of the SMO metamaterial‐based computation is to create a new test image dataset by adding noise to the standard digit figures; samples are shown in the right panel of Figure  Nevertheless, this method requires the integration of electronic components and lacks the potential to evolve into in‐memory computing. Furthermore, achieving these functionalities within the realm of mechanical computing is exceedingly rare, thus underscoring the originality of our work.It's noteworthy that the utilization of memristors in the reservoir computing approach can yield a comparable recognition effect, albeit with enhanced efficiency.41 Nev2.2In addition to the computer‐generated images of digits, more realistic and sophisticated images are considered to test the learning ability of the SMO metamaterial‐based computational framework. To this end, we use a training and testing database widely employed in the field of machine learning, called the Mixed National Institute of Standards and Technology database (MNIST). The MNIST database is composed of 60 000 training images and 10 000 testing images. To relieve the training burden, we take a reduced set of random portion of these training and testing images, respectively. We will show later that although the reduction of training samples will affect the recognition accuracy, the SMO metamaterial‐based computational framework is still effective.χ∈RM×1, whose elements χi  take values of 1 or –1, representing the transition under tensile or compressive loading, respectively. The dimension M represents the number of transitions. Based on this model, the learning capability of the SMO metamaterial can be effectively explored, and the readout weights can be trained.Here, the training and testing of the SMO metamaterials are implemented by simulations. For this purpose, a mechanical model of the SMO metamaterial with an arbitrary number of component cells is developed  but faster in the same handwritten digit recognition task. However, what distinguishes this approach is the integration of mechanical structures to realize nonlinear transformations. While the accuracy is somewhat diminished due to a reduced dataset , it represents a major breakthrough in the field of mechanical learning. This breakthrough greatly reduces the demand for electronic computation (only a linear readout layer is required), potentially enabling more intelligent mechanical systems.Note that pure machine learning methods can achieve recognition accuracies of 99% or higher, and such accuracies continue to improve.42 HowWe further examine the effects of crease stiffness and actuation rules on the computational results of the SMO metamaterial. Five distinct SMO chains with different crease stiffness  and four binary output channels . The first two input channels in the first 5 time steps carry a prescribed pattern with either x1 or x2 set to 1 and the other set to 0. An example is highlighted with shade in Figure x3 is set to 1. In this specific case, we set the duration period to be 4 time steps. The fourth input channel carries the cue: when x4 = 1, x3 = 0, and it is the time for the first two outputs to repeat the pattern prescribed in the first five time steps. After the cue, x3 is set to 1 again. The output channels y1, y2 are always 0 before the last 5 time steps, while y3 remains 1 until the cue is recalled. The fourth output channel y4 is unused and is always set to 0.As a benchmark test of sequential learning, the 5‐bit memory problem24 is Specifically, in this learning task, the SMO metamaterial is asked to “remember” the input pattern of the first 5 time steps and reproduce it in the last 5 time steps; this is achieved by integrating recursive loops in the computational framework. In detail, the constituent cells of the SMO metamaterial are divided into two different zones: the writing or rewriting zone that is responsible for encoding the binary input into the SMO metamaterial, and the buffer or memory zone that consists of more SMO cells than the input dimension to store the historic information Figure . To implThe 5‐bit memory problem is carried out via the same SMO metamaterial as in Figure The variance brought by the uncertainty of the structural properties is also investigated. To this end, five SMO metamaterials with different crease stiffness  Geometry‐Induced Mechanical Properties: the mechanical properties of origami metamaterials were primarily derived from folding geometry rather than the properties of constituent materials. This fundamental property makes the origami metamaterials “scale‐independent,” meaning that they can be engineered from the nanoscale to the macroscale. This unique feature holds the promise of adapting the mechanical computing framework across various scales, thus supporting its potential scalability and broader applicability; 2) Periodicity: notably, the periodicity of origami metamaterials facilitates their assembly from basic unit cells. This inherent periodicity opens the door to infinite scalability, allowing the metamaterials to seamlessly scale to large configurations. Such intrinsic scalability further enhances to the scalability of this approach, allowing it to be integrated into a wide range of computational systems. By emphasizing these traits, future work will comprehensively demonstrate how the mechanical computing framework, rooted in origami metamaterials, inherently supports cross‐scale and cross‐configuration scalability. Nevertheless, achieving significant scalability demands careful attention to fabrication and integration processes, which were ongoing areas of exploration.Envisioning practical applications, a structure's scalability becomes paramount. This underpins our choice of the origami metamaterial, which possesses dual traits ensuring its scalability:46 1) 3.4While the current focus centers on showcasing the feasibility of the proposed framework at the device level, the potential for system‐level implementation was undoubtedly an exciting avenue for exploration. This involves several key aspects: miniaturizing and fabricating origami metamaterials at a larger scale to underpin system scalability, developing automated actuation mechanisms for seamless configuration transitions, and integrating sensors for real‐time feedback to enhance monitoring and control. It was crucial to underscore that although these components were presently in separate phases, the inherent feasibility of each component fosters a sense of optimism for their eventual integration. While acknowledging the potential challenges inherent in the development of a fully operational system, it remains clear that these obstacles could be effectively addressed through dedicated research and continuous refinement.3.5Despite the confirmation that minimal variances in mechanical performance do not impact the configuration transitions as well as the computation capability, the potential for extensive and repetitive real‐world utilization underscores the importance of addressing concerns related to mechanical fatigue and structural damage. This was particularly crucial as it directly influences the determination of the operational lifespan of the mechanical computing device. Considering this, ongoing research was focused on further exploring these aspects, thereby ensuring the robustness and reliability of the mechanical computing paradigm.3.6In this paper, it had demonstrated that a simple origami‐inspired structure possesses the remarkable capabilities of image recognition and temporal memory. This underscores the intriguing potential that complex functionalities like perception, memory, and decision‐making could be accomplished by simple mechanical frameworks. This breakthrough prompts us to envision a future in which the intelligence of robots does not solely rely on a centralized electronic brain. Instead, robots could leverage the inherent mechanical properties of their bodies to perceive, remember, and even respond to the external environment, thus realizing a greater level of autonomy and intelligence. This departure from conventional paradigms holds the promise of revolutionizing the field of robotics and artificial intelligence, inspiring novel avenues for research and development, and ultimately leading us toward more adaptable and intelligent machines.4Multistable origami metamaterials are highly comparable to cellular automata in terms of constituent cells, stable states, transition sequences, and dimension extension capability. This inspired us to create a physical analogue of cellular automata using origami metamaterials, with which the demanding requirements for fabrication of material counterparts and signal propagation when constructing large‐scale networks for high‐level computation in conventional mechanical logic can be addressed, and complex computational tasks can be realized with simpler structures. Under external stimulation, the analogue displays rich transition sequences, which can serve as a reservoir for functions similar to nonlinear transformation and signal processing. We experimentally illustrate the computational power of the SMO metamaterial with a digit recognition problem. For more complex tasks, such as handwriting recognition and 5‐bit memory tasks, the effectiveness is tested via simulations.5Figure The prototype composed of 4 × 2 SMO cells is fabricated by the dual‐material 3D printing technique based on a commercial multi‐material printer (Ultimaker S5), demonstrated in To effectively facilitate the experimental configuration transition of the SMO metamaterial prototype, we have meticulously designed a specialized device, as illustrated in Figure The authors declare no conflict of interest.Supporting InformationClick here for additional data file.Supplemental Movie 1Click here for additional data file.Supplemental Movie 2Click here for additional data file.


Parkinson's disease is a neurodegenerative disorder predominately affecting midbrain dopaminergic neurons that results in a broad range of motor and non‐motor symptoms. Sleep complaints are among the most common non‐motor symptoms, even in the prodromal period. Sleep alterations in Parkinson's disease patients may be associated with dysregulation of circadian rhythms, intrinsic 24‐h cycles that control essential physiological functions, or with side effects from levodopa medication and physical and mental health challenges. The impact of circadian dysregulation on sleep disturbances in Parkinson's disease is not fully understood; as such, we review the systems, cellular and molecular mechanisms that may underlie circadian perturbations in Parkinson's disease. We also discuss the potential benefits of chronobiology‐based personalized medicine in the management of Parkinson's disease both in terms of behavioural and pharmacological interventions. We propose that a fuller understanding of circadian clock function may shed important new light on the aetiology and symptomatology of the disease and may allow for improvements in the quality of life for the millions of people with Parkinson's disease. In Parkinson's disease, pathological α‐synuclein aggregation and Lewy body formation may lead to the death of dopaminergic neurons, which has a bi‐directional influence on circadian rhythm dysfunction and sleep disturbances. L‐dopa treatment and dopamine agonists may also influence circadian rhythm dysfunction. Sleep disturbances such as social jet lag/shift work can have a bi‐directional influence on circadian rhythm dysfunction. Healthy ageing results in changes in circadian function in older adults, including reduced circadian rhythm amplitude in sleep–wake cycles, advanced circadian phase and earlier chronotype, more inter‐daily variability in activity cycles and altered circadian responses to light Duncan, . Older aIt is of interest to examine the circadian and sleep changes associated with other neurodegenerative conditions to appreciate transdiagnostic features of sleep and rhythm disturbances across such conditions vs diagnosis‐specific changes. Circadian rhythm changes observed in age‐related neurodegenerative conditions, such as Alzheimer's disease (AD), are found to be markedly more pronounced than those observed in healthy ageing , sleep fragmentation, decreases in the quantity of non‐rapid eye movement (NREM) sleep, low sleep efficiency and excessive daytime sleepiness (EDS) Comella, . These sInterestingly, aside from neurodegeneration in the substantia nigra, loss of non‐dopaminergic neurons, such as hypocretin, norepinephrine and serotonin‐releasing neurons, is also associated with sleep disturbances in PD patients. For example, the early onset of narcolepsy‐like sleep manifestations, such as frequent wakening and daytime sleepiness, in PD patients may originate partially from loss of hypocretin neurons in the hypothalamus, and the rate of loss of hypocretin neurons increases with advancing Braak staging of PD neuropathology  and is characterised by recurring instances of the collapse of the upper airway during sleep leading to apnea and hypopnea , a biomarker for the circadian clock phase, in PD patients has demonstrated that the phase angle of entrainment (the discrepancy between circadian phase and sleep/activity onset) is larger in PD patients on medication compared to PD un‐medicated patients, indicating a role for PD medication in alterations of melatonin rhythms and the relationship between the circadian and the sleep–wake cycles, in that dopaminergic therapy was associated with delayed sleep onset relative to the circadian phase as estimated by DLMO , which is regulated by competition between rev‐erbα and nuclear receptor‐related 1 protein (nurr1) ’ effect, wherein symptoms recur whilst medication is wearing off in the morning and occurs in more than 50% of PD patients receiving dopaminergic treatment (Han et al., If L‐Dopa treatment is associated with sleep and circadian rhythm disturbance, then chronotherapy, such as the use of light therapy and/or melatonin treatment, may be useful treatment adjunct to minimise such effects (Fifel & Videnovic, 8Drosophila Melanogaster that translated to the understanding of the genetic basis of familiar circadian rhythm sleep disorders (Huang, Conducting circadian rhythm research in human populations brings many challenges, including achieving adequate statistical power, clinical heterogeneity of study samples, limitations on the period of sleep–wake monitoring and the high demand characteristics for sampling regimes required for assays of rhythmic biomarkers, environmental variables and social factors and transcultural differences in daily schedules and norms and difficulties in attaining mechanistic insights or establishing causality in relationships (Blatter & Cajochen, s Huang, . As suchStudies on a transgenic mouse model of PD that overexpressed the SNCA gene that encodes α‐synuclein demonstrated some alterations in sleep and circadian rhythm parameters, including a reduction in the firing rate of SCN neurons, dampened circadian rhythms with ageing and disease progression and a significant increase in sleep onset latency following a lower power in circadian rhythm (Kudo et al., bmal1, per2 and clock genes, which were decreased in this model, but the transcription of rorα was increased and acetylation of bmal1 promoter was increased due to the reduction in NAD‐dependent deacetylase sirtuin‐1 (Wang et al., BMAL1 transcription (Li et al., bmal1 or a phase advance in per1 expression (Mattam & Jagota, The effect of age‐related degeneration of dopaminergic neurons on the lengthening of the circadian period in the absence of circadian amplitude alteration was shown in a study with the neurotoxic MPTP mouse model, indicating that PD‐like circadian phenotypes might not be confined to decreased rhythm amplitude and/or robustness (Tanaka et al., An important question that may be partially answered using pre‐clinical models is the extent to which circadian rhythm changes in PD models resemble those abnormalities reported in pre‐clinical models of other neurodegenerative conditions (Nassan & Videnovic, 9To systematically describe on a multi‐modal level the nature of circadian rhythm changes that precede, and occur in, PD. Such assessments may involve longitudinal samples in well‐powered studies that embrace clinical heterogeneity rather than try to ‘control’ it away. Further, delineating the circadian impacts of PD pathology from the circadian impacts of PD medication will be key in identifying practical steps that may be taken to improve circadian function and sleep health in PD patients.The literature on circadian rhythms and PD, like in many adjacent areas, is currently dominated by relatively small studies with inconsistent protocols between studies (e.g., Huang et al., Clinical studies should be systemically coordinated with studies in pre‐clinical PD animal models. Animal models have great potential to augment and complement clinical studies, but their use needs to be carefully considered in the design of studies. Such work may include the adoption of standardized protocols across collaborating sites, the use of several models to uncover commonalities that may be the most relevant to PD rather than ‘one off’ observations in single models that may not well recapitulate the clinical picture of PD, the use of both male and female mice to avoid bias and the use of mice across all life stages. Furthermore, for the use of transgenic mouse model consideration needs to be given to the background strain, as there can be large differences in circadian function in wild‐type animals between commonly used in‐bred strains (Schwartz & Zimmerman, The circadian system is a highly distributed one that exerts a pervasive influence across physiological systems and as such may impact PD through a variety of systems and processes. For example, much attention is currently directed to the role of the gut microbiome in brain health and disease (Cryan & Mazmanian, How does real‐world circadian disruption affect PD risk? It is recognized that a large proportion of the population lives under social and working conditions that result in circadian rhythm disturbance (Lunn et al., Further, develop and validate actigraphic and wearable device procedures and scoring algorithms for their use specifically in PD. As most actigraphic scores are validated in healthy cohorts, it is currently unclear as to how the motor symptoms of PD may impact measures derived from those processes. As such, there should be a focussed effort on validating established actigraphic procedures and new and emerging technologies specifically within the clinical context of PD.Circadian perspectives are gradually becoming a mainstream consideration in medicine (Kramer et al., 10Circadian rhythm disturbances in PD appear to be common, may be important contributors to other sleep disorders and problems in PD such as insomnia and excessive daytime sleepiness and may be exacerbated by dopaminergic therapy for PD. Such circadian dysfunctions may be tractable through the application of circadian medicine, but to advance this important area, a coherent research agenda will be needed to develop the depth and quality of the research evidence base to the point that clinical practice can be informed and advanced for better patient outcomes.The authors declare that there are no conflicts of interest.Beverley M. Henley and Andrew N. Coogan conceived the idea. Ziba Asadpoordezaki, Andrew N. Coogan and Beverley M. Henley researched the literature and wrote the review article.11https://publons.com/publon/10.1111/ejn.15859.The peer review history for this article is available at


Even the simplest cells show a remarkable degree of intracellular patterning. Like developing multicellular organisms, single cells break symmetry to establish polarity axes, pattern their cortex and interior, and undergo morphogenesis to acquire sometimes complex shapes. Symmetry‐breaking and molecular patterns can be established through coupling of negative and positive feedback reactions in biochemical reaction‐diffusion systems. Physical forces, perhaps best studied in the contraction of the metazoan acto‐myosin cortex, which induces cortical and cytoplasmic flows, also serve to pattern‐associated components. A less investigated physical perturbation is the in‐plane flow of plasma membrane material caused by membrane trafficking. In this review, we discuss how bulk membrane flows can be generated at sites of active polarized secretion and growth, how they affect the distribution of membrane‐associated proteins, and how they may be harnessed for patterning and directional movement in cells across the tree of life. Sites of polarized secretion induce lateral bulk plasma membrane flows. Peripheral proteins with fast unbinding and lateral diffusion dynamics can repopulate secretion sites. By contrast, peripheral proteins with long‐enough membrane residence time couple to these flows and are displaced from secretion zones. This phenomenon can be harnessed by the cell for self‐organization. CIBNN‐terminus of CIB1 proteinCRY2cryptochrome 2The plasma membrane, which delimits the cell from its environment, is a highly specialized organelle where functional domains are formed through the spatial organization of lipids and proteins. Although membrane domains may appear stable through time, plasma membrane components continually turn over. In eukaryotic cells, a major form of turnover takes place through endo‐ and exocytic routes that retrieve and deliver vesicles from and to the plasma membrane, respectively. Many cell types exhibit highly polarized zones of secretion, where new membrane is added from internal pools at high rate. Examples include the tip of polar‐growing cells like fungi or pollen tubes, where cell wall remodeling enzymes are secreted; B and T cell immunological synapses, where cytolytic enzymes are released; the leading edge of migrating cells and growth cones, where adhesion molecules must be delivered; neuronal synapses, where secretion of information‐containing neurotransmitters takes place or the apical domain of exocrine cells. Because the composition of secretory vesicle membranes is not identical to that of the plasma membrane, the massive incorporation of secretory vesicles is a perturbing factor for plasma membrane homeostasis. How does the cell deal with this incorporation and what effect does the process have on the composition and spatial organization of the plasma membrane?In this viewpoint article, we discuss how polarized secretion triggers bulk plasma membrane flows away from the secretion zone. We first present our recent findings in the simple fission yeast, where polarized secretion causes in‐plane bulk membrane flows away from the secretion site, with important consequences on the distribution of membrane‐associated proteins and cell morphogenesis. We then discuss conditions necessary to generate membrane flows, the effect flows have on membrane‐associated proteins and how this phenomenon may be used in cells to generate functional patterns.Schizosaccharomyces pombe grows by tip extension forming rod‐shaped, walled cells. The cell poles and medial division site are regions of new membrane and cell wall material delivery by polarized secretion. Using the CRY2‐CIBN optogenetic system, we recently revealed bulk membrane flows from secretion sites [The fission yeast on sites . In our Membranes can be considered as 2D incompressible fluids. Thus, new membrane addition will lead to expansion of the membrane surface area. Whether a secretion site generates bulk membrane flows depends on two general conditions. First, the plasma membrane must be under an overall background in‐plane tension such that new membrane addition does not lead to formation of a fold but to displacement of the pre‐existing membrane away from the site of insertion. Second, to create directional flow under homeostatic conditions, retrieval of excess membrane by endocytosis must occur in a region wider or distinct from the site of membrane insertion, a setup prevalent across cell types  the plasma membrane is under significant tension – in electron micrographs, it generally appears as a flat surface pressed against the cell wall by the strong internal turgor pressure; and (b) walled cells do not harbor an actomyosin cortex. Tip‐growing walled cells (for instance many fungi and plant cells such as pollen tubes or root hairs) exhibit highly polarized secretion at their growing pole(s), which leads to a substantial excess of membrane exocytosis relative to the amount of new membrane required for cell growth, perhaps required to deliver sufficient cell wall remodeling material. In fission yeast cells, we and others estimated a 75–80% excess , 2, witha crassa . Similarr region , 6; in Smergence ). Similamergence , but themergence , 12, sugDrosophila neuromuscular junctions, the endocytic machinery surrounds sites of secretion for synaptic vesicle recycling [Large‐scale exocytic events are a hallmark for a number of specialized metazoan cells. Examples include neuronal growth cones and synapses, immunological synapses or exocrine cells. There is clear evidence of endocytosis‐exocytosis spatial coupling at the neuronal synapse where exocytic vesicles localize to active zones surrounded by endocytic vesicles  Fig. 2B2B. In Drecycling , at setuecycling  and fronecycling . Though Targeted vesicular trafficking is also critical for the process of cell division in all organisms . In yeasWhile distinct distribution of exo‐ and endocytic activities may drive in‐plane membrane flows , cells can also resolve the destabilization caused by large‐scale membrane insertion in other ways. Solutions to this problem include kiss‐and‐run mechanisms in neurons, where the vesicle only briefly fuses with the plasma membrane to release its content but reseals before membrane integration (reviewed in ), or vesA hypothesis of bulk retrograde membrane flows driving metazoan cell migration was first formulated by . In thisHowever, the notion of such a ‘fluid drive’ is not universal , for twoWhat is the effect of membrane flows on the distribution of membrane‐associated proteins? In general, flows are predicted to influence the steady‐state distribution of proteins, depending on their residence time at the plasma membrane and on their relative abundance in vesicles and the plasma membrane .v over length scale L, proteins that exhibit diffusion coefficients smaller than v·L and detachment rates smaller than v/L will be depleted from the secretion site [In the simplest situation, the protein associates specifically with the plasma membrane but does not bind transport vesicles, such that secretion indeed adds ‘naked’ membrane. This is the case of many proteins that associate peripherally with the plasma membrane, for instance through amphipathic helices or other lipid‐binding domains. Such proteins do not depend on vesicular trafficking but dynamically exchange between cytosol and membrane, with a steady‐state distribution that depends on membrane‐binding and unbinding rates. Proteins that exhibit fast unbinding rates can populate the ‘naked’ membrane at the secretion site fast enough to display a homogenous distribution irrespective of bulk membrane flows. By contrast, proteins with a long membrane residence time, due to slow unbinding rates or slow lateral mobility, couple with membrane flows and become displaced from sites of new membrane addition. Indeed, increasing membrane residence time through simple tandem dimerization of a membrane‐binding domain is sufficient to convert a homogeneous localization to one depleted from secretion sites . Quantition site   that localize to cell sides and inhibit Cdc42, including the GAP Rga4, whose localization is likely patterned by membrane flows . By consArabidopsis pollen tubes. REN4 functions as a negative regulator of ROP1, by promoting its endocytic retrieval in the sub‐apical zone, thus limiting the active ROP1 zone. Interestingly, REN4 associates with the apex of non‐growing pollen tubes but is displaced laterally in growing tubes [There is an intriguing parallel between Cdc42 GTPase regulation by the Rga4 GAP in fission yeast and ROP1 GTPase regulation by the recently described REN4 protein in ng tubes . It willS. cerevisiae [S. cerevisiae, the Rab GTPase Sec4, which promotes the tethering of secretory vesicles with the plasma membrane, also activates actin polymerization for endocytosis, thus promoting endocytic events in the vicinity of exocytic sites [We hypothesize that many protein localizations and morphogenetic events are shaped by membrane flows. These may include the sculpting of the septin ring by exocytosis and establishment of daughter cell identity in revisiae , or the revisiae . An inteic sites . In the ic sites , with siic sites . As manyThe authors declare no conflict of interest.VG and SGM co‐wrote the manuscript and designed the figures.All data is available within the article.