Movement, from foraging to migration, is known to be under the influence of the environment. The translation of environmental cues to individual movement decision making is determined by an individual’s internal state and anticipated to balance costs and benefits. General body condition, metabolic and hormonal physiology mechanistically underpin this internal state. These physiological determinants are tightly, and often genetically linked with each other and hence central to a mechanistic understanding of movement. We here synthesise the available evidence of the physiological drivers and signatures of movement and review (1) how physiological state as measured in its most coarse way by body condition correlates with movement decisions during foraging, migration and dispersal, (2) how hormonal changes underlie changes in these movement strategies and (3) how these can be linked to molecular pathways.We reveale that a high body condition facilitates the efficiency of routine foraging, dispersal and migration. Dispersal decision making is, however, in some cases stimulated by a decreased individual condition. Many of the biotic and abiotic stressors that induce movement initiate a physiological cascade in vertebrates through the production of stress hormones. Movement is therefore associated with hormone levels in vertebrates but also insects, often in interaction with factors related to body or social condition. The underlying molecular and physiological mechanisms are currently studied in few model species, and show –in congruence with our insights on the role of body condition- a central role of energy metabolism during glycolysis, and the coupling with timing processes during migration. Molecular insights into the physiological basis of movement remain, however, highly refractory. We finalise this review with a critical reflection on the importance of these physiological feedbacks for a better mechanistic understanding of movement and its effects on ecological dynamics at all levels of biological organization. An individual-based view on organismal movement as propounded by the Movement Ecology Paradigm (MEP) has provoked a breakthrough in movement ecology as it links the biomechanical and behavioural basis of movement to fitness . The MEPThe Fundamental Movement Elements (FME) form the smallest unit of organismal movement and include for instance step size and wing beat frequency. The FMEs hence depend directly on the motion capacity and internal state components Fig.  and mechIndividuals make decisions to switch between CAMs in response to both the environmental context and internal state. As the sequence and variation in FME’s are strung into an organism’s CAM, any decision made regarding shifts in these CAM’s will depend on an individual’s internal state (and navigation capacity). Because resources are rarely homogeneously distributed in the environment and often continuously changing in time as well, movement will be essential to gain access to resources  and will directly impact the individual’s internal state. This feedbacks between an individual’s immediate environment and its internal state will therefore shape its lifetime movement trajectory and fitness .The maximisation of energy balances forms the basis of optimal foraging theory and directly links an individual’s energetic state (body condition) to routine foraging activities , 4. WhilUnderstanding the causes and consequences of the variation in movement trajectories has been identified as an important knowledge gap in movement ecology . As a fiThere is an abundant body of literature on how different movement strategies are related to metrics of body condition. Body condition is predominantly measured in a coarse way by residual or absolute body mass. The efficiency and pace of foraging movements are mostly positively related to a better body condition –21. A goPasser domesticus), lower ranked individuals leave natal areas earlier than their conspecifics that occupy higher positions in the social hierarchy )cal mass . Feedbaccal mass . Moreovecal mass . Given tBody-condition dependent strategies are often overruled by hormonal changes in response to acute biotic and abiotic stressors . We hereIn vertebrates, external triggers of movement decisions such as food shortage, fear and antagonistic interactions with conspecifics are known to initiate a physiological cascade through the hypothalamic-pituitary-adrenal (HPA) axis by which stress hormones  are released from the adrenal cortex. Creel et al.  provide Food shortage and social interactions attenuate foraging activity through hormonal regulation in birds –88. ElevLuscinia luscinia), elevated CORT-levels are modulated by geomagnetic information [Erithacus rubecula) CORT-levels differ between spring and autumn migration [Junco hyemalis), genetic variation in these responses was found among two populations overwintering in areas that varied in the level of environmental predictability [Baseline plasma CORT levels are elevated in migrating birds to facilitate migratory fattening while protecting skeletal muscle from catabolism, but they also induce health costs –100. Theormation ; and in igration . CORT-letability . More sptability . Althougtability –110.Diabrotica virgifera) [Oncopeltus fasciatus) [Danaus plexippus), migration necessitates the persistence through a long winter season. This prolonged survival has been shown to result from suppressed JH synthesis [Octopamine and adipokinetic hormones are known to regulate energy supply, the oxidative capacity of the flight muscles, heart rate, and probably also a general stimulation of the insect nervous system during periods of intense flight . Octopamrgifera)  and milksciatus) . In migrynthesis .As outlined above, the dependency of movement strategies on body condition is highly complex and multidimensional, rendering the characterization of the underlying molecular and physiological mechanisms highly refractory. Traditionally, the contribution of candidate genes to foraging, dispersal, and migration behavior has been studied in isolation. We briefly discuss genes of major effect on different movement strategies and subsequently attempt to unify the molecular drivers of movement.Colias butterflies and that their frequencies change in response to heat stress [pgi gene have subsequently been detected in many insect populations and species [pgi the ideal candidate gene to study the genetic underpinnings of dispersal ability [Melitaea cinxia) metapopulation on the Åland island group [Phosphoglucose isomerase (PGI) is an important metabolic enzyme that catalyzes the reversible second step within the glycolytic pathway. In a series of pioneering studies, Watt and colleagues discovered that different allozymes  of PGI have different thermostabilities in t stress –122. Pol species –125. Its ability , 127, asnd group –131. Curnd group ) identifnd group .Drosophila melanogaster where differences in food searching behavior of larvae were mapped to a locus on chromosome-2 called the foraging (for) gene [for gene have been studied as a potential causal factor in behavioral transitions in the nematode Caenorhabditis elegans, honeybee Apis mellifera, and two ant species [Amfor and egl-f, orthologs in honeybees and C. elegans, respectively, food dependent movement is significantly altered in both species [The central role of a cGMP-activated protein kinase (PKG) in foraging behavior, adult dispersal and perception of nutrient stress in a wide diversity of insect species was initially discovered in the fruit fly or) gene –139. It  species –143. For species , 144.OtsClock1b and Adcyap1 are not only associated with differences in timing and distance of migration but also affect morphology, hormone production and timing of reproduction [Danaus plexippus) differ in the Collagen IV alpha-1 gene, which participates in muscle development, metabolism and circadian rhythm pathways [Clock genes are involved in the timing and onset of migration in birds, fish and butterflies –147. Alloduction , 149. Repathways , 151. ThAlthough these candidate genes seem to be key regulators for movement behavior, they fail to provide us with a complete insight into the often complex genetic architecture of common traits underlying movement. To overcome this limitation, more pathway-oriented and genome-wide methodologies are now being applied in movement ecology. Advances in –omics technologies not only provide biologists with knowledge concerning the genome-wide gene content of many non-model species, but also the unbiased quantification of transcription by transcriptomics.Melitaea cinxia) that inhabit either fragmented or continuous landscapes. These different expression profiles may indicate selection for certain variants in genetic pathways that are involved in successful dispersal in fragmented landscapes [D. melanogaster showed that the for gene at least partially operates through the insulin/Tor signaling pathways, which are regulatory pathways that control animal growth, metabolism, and differentiation [D. melanogaster larvae with a long movement path  store energy reserves mainly as lipids while individuals with shorter movement paths (sitters) store energy as carbohydrates [Danaus plexippus), no differential expression of the for gene was observed [Using a transcriptomic approach, Somervuo et al.  found a ndscapes . Notablyndscapes . Other tndscapes . Transcrntiation , 154. Inhydrates , 137. Inhydrates . While Jobserved .Turdus merula) it was shown that, prior to departure, many genes rapidly change their transcription and these genes are predicted to participate in cholesterol transport and lipid metabolism [Marmota flaviventris), transcriptomic data shows that the differences between dispersers and resident individuals lie in the upregulation of the metabolism and immunity [In birds and mammals, transcriptomics offers a new approach to study migration and dispersal by extracting blood from individuals before and after the movement type of interest and comparing RNA profiles. Although this analysis likely excludes important signals from other organs such as the liver and brain, it can offer key insights into molecular mechanisms related to the behavioral decision making of movement. In blackbirds (tabolism . In marmimmunity .Tetranychus urticae) that show genetic variation in dispersal along a latitudinal gradient, metabolomic profiling indicated that an allocation of energy could be linked to a dispersal-foraging trade-off, with more dispersive mites evolving to cope with lower essential amino acid concentrations thereby allowing them to survive with lower amounts of food [Drosophila that were artificially selected for increased dispersal, higher amounts of octopamine and serotonin were detected [Transcriptomic analyses hold great promise to find common underlying molecular pathways that relate to certain types of movement behaviors, but it remains difficult to connect different transcriptomic profiles to the exact levels of metabolite production . In plan of food , 160. Th of food . In Drosdetected . These ndetected , 163. Ocdetected .Danaus plexippus) and recorded changes in migration behavior. Future work needs to incorporate similar gene-editing approaches to advance our understanding of the genetic architecture underlying movement behavior [No individual genes or single pathway clearly stand out from these metabolomics and transcriptomics studies. To causally link genes to movement, novel gene-editing techniques such as CRISPR/Cas9 technology has now made it possible to modify specific loci within the genomes of many organisms in a stable manner . Gene-edbehavior .Environmental change imposes physiological changes, but as these determine movement and hence suceptability to these environmental stressors, emerging feedbacks are expected at different levels of biological organisation. First, our synthesis made clear that carry-over effects between the movement modes (CAMs) are very likely. Environmental conditions constraining local foraging will eventually impose physiological changes that limit the efficiency of dispersal and migration events, and reciprocally, any excessive energy expenditure or exposure to additional stressors  during these long-distance journeys can carry over to foraging movements in the subsequent resident stages .Gyrinophilus porphyriticus) was found to maintain positive growth in putative sinks, hence, contributing to form of self-organisation in these linear habitats [As these physiological changes are anticipated to be correlated with demographic traits and behaviours, hence forming behavioural syndromes , 81, 170habitats .Ricketsia endosymbionts are for instance found to constrain spider dispersal behaviour [The impact of body-condition dependent movement on community structure has been mainly studied from a co-dispersal perspective, i.e., when hosts in a specific physiological state are moving symbionts. The best-documented consequences of such physiological-induced individual differences are related to the quantity and quality of endozoochorously dispersed seeds by vertebrates . At the ehaviour , while tehaviour .Our understanding of the relative importance of movement-physiology feedbacks in population and community dynamics is still developing. It is nevertheless clear from our review that human-induced rapid environmental changes will affect this eco-physiological nexus, and that the integration of multiple theoretical frameworks may be required to explain the observed variation in movements in nature . UnderstUnbiased genome-wide transcriptomics using RNA-seq has become very popular in the last couple of years to study movement phenomena , 189–191We obviously applaud this direction as it will advance our understanding of spatial population dynamics substantially from an individual, mechanistic perspective. However, an open question, remains to what extent such highly detailed studies of the physiology of movement are needed or desirable to transform the field of movement ecology towards a more predictive science. It is clear from our review that physiological control mechanisms constrain and dictate variation in how animals with different movement strategies respond to its surrounding environment. The physiological control of movement should therefore be treated as a reaction norm, and as for models including feedbacks between evolution and ecology , we expeWhether such a theory needs to extend into the molecular pathways underlying the physiology of movement, is more questionable. While this perspective has been recently brought forward within the framework of a predictive ecology in response to climate change , our revModelling approaches that explicitly account for metabolic costs associated with movement and costs associated with risk-taking might already provide general insights on how feedbacks between the environment and physiology eventually shape movement strategies and their coexistence across and within populations . OEnvironments are spatiotemporally heterogeneous, either because of external abiotic drivers or because of internal biotic dynamics. As organisms need to maximise fitness, their movement behaviour should be optimised. Failing to do so might lead to physiological states that constrain such adaptive shifts. Our review demonstrates the central importance of body condition or energetic state as a driver of movements at different spatiotemporal scales, from foraging to dispersal and migration. Overall, as body condition is determined by carry-over effects from early life, we show the importance of these early conditions for physiology and subsequent movement decision making. Negative relationships between movement and body condition become more common with increasing costs of movement. As a decision-making process, the onset of movement at these different spatiotemporal scales is associated with hormonal and gene-expression changes as well. These insights are merely derived from classical model systems and allow a profound insight into the physiological pathways, and the putative correlated responses on other traits and performance. It is, however, clear that much more work is needed to achieve sufficient progress in the field to develop a unifying synthesis on the link between environmental change, physiology and the resulting feedbacks on ecological dynamics. We encourage endeavours in this direction and are hopeful because of the accelerating rate at which new methodologies are developed. However, given the infancy of a physiological movement ecology and the urgency to develop a predictive model of biodiversity in response to environmental change, we advocate a cost-based modelling approach that considers movement decision thresholds in relation to basic physiological states as an important step forward. Ideally, such modelling approaches are centred on physiological dynamics caused by key-molecular pathways, that link environmental change to the condition-dependency of movement across the relevant spatiotemporal scales.How variable are body-condition dependent thresholds across contexts and environments, and to which degree do they underlie heterogeneity in movement strategies within and across populations?What is the impact of these threshold responses on population dynamics and vice-versa?When are these body-condition dependent movements overruled by hormonal processes ?As metabolic processes and movement allometrically scale to body size, are condition-dependent strategies variable among species of different size, or even trophic levels (e.g. see )?Questions related to movement-decisions that depend on body condition.How are physiological processes that are central in life history and behavior at the basis of movement syndromes, i.e. how do movement strategies correlate with life histories and other behaviour?How are these correlations shaped by the inter- and intraspecific interactions?To what extent can microbial symbionts influence and shape these correlations and movement strategies?Questions related to movement syndromesAre there generic molecular pathways that underly many different movement strategies and are they regulated by the same genes and hormones in different species?Is there a common genetic background for movement syndromes, and strategies across all life stages?Questions related to genes underlying movement-decisionsKnowledge caveats hinder the development of a movement ecology that integrates detailed physiological feedbacks in terms of the underlying molecular networks. It remains to be investigated whether and how much the integration of first principles that underlie physiological changes of movement, as to be developed by the next generation of theory, improve the predictive power of ecological forecasting models. Here we summarise the outstanding questions related to the main topics that are discussed in this paper.


Telemonitoring of Parkinson’s Disease (PD) has attracted considerable research interest because of its potential to make a lasting, positive impact on the life of patients and their carers. Purpose-built devices have been developed that record various signals which can be associated with average PD symptom severity, as quantified on standard clinical metrics such as the Unified Parkinson’s Disease Rating Scale (UPDRS). Speech signals are particularly promising in this regard, because they can be easily recorded without the use of expensive, dedicated hardware. Previous studies have demonstrated replication of UPDRS to within less than 2 points of a clinical raters’ assessment of symptom severity, using high-quality speech signals collected using dedicated telemonitoring hardware. Here, we investigate the potential of using the standard voice-over-GSM (2G) or UMTS (3G) cellular mobile telephone networks for PD telemonitoring, networks that, together, have greater than 5 billion subscribers worldwide. We test the robustness of this approach using a simulated noisy mobile communication network over which speech signals are transmitted, and approximately 6000 recordings from 42 PD subjects. We show that UPDRS can be estimated to within less than 3.5 points difference from the clinical raters’ assessment, which is clinically useful given that the inter-rater variability for UPDRS can be as high as 4–5 UPDRS points. This provides compelling evidence that the existing voice telephone network has potential towards facilitating inexpensive, mass-scale PD symptom telemonitoring applications. I.bradykinesia (slow and reduced amplitude of movement), rigidity (resistance to passive movement), and tremor (while at rest) Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by the progressive deterioration of motor function as well as the emergence of considerable non-motor problems Medication and surgical intervention can alleviate some of the symptoms and improve quality of life for most PWP motor-UPDRS, which is a subset and highly correlated with the total UPDRSIn current clinical practice, medical raters physically examine PWP and map symptom severity on appropriate clinical scales (metrics). The Unified Parkinson’s Disease Rating Scale (UPDRS) Speech disorders, which are of particular interest in this study, may be amongst the earliest PD onset indicators At-Home Testing Device (AHTD) Most PD studies rely on the use of expensive, purpose-built specialized hardware to record signals which are characteristic of PD symptoms, e.g. et al.In this study, we investigate whether it is possible to accurately infer UPDRS using speech signals transmitted over the standard cellular mobile voice telephone network, using a detailed simulation of the entire digital communication process. The rationale for using the existing voice mobile phone network over specialized, purpose-built hardware such as the AHTD is that (a) the existing voice network reaches nearly 75% of the global population, (b) economies of scale and global market competition has brought the price of access down so that it is affordable to a majority of the global population, (c) mobile telephony allows freedom of movement for PWP, eliminating the need to carry additional equipment when leaving home. Thus, the standard phone network provides convenient means towards inexpensive and frequent PD severity assessments, facilitating monitoring and potentially assisting rehabilitation. Data-mining of speech signals obtained using the public telephone network to extract clinically useful information has recently shown promising results We demonstrate that mobile phone technology could be useful in telemonitoring PD symptom severity, further endorsing previous findings that speech may offer a convenient framework for remote assessment II.et al.et al.We use the voice data collected by Goetz Previously, we demonstrated that partitioning the data by gender is important in this application Six sustained vowel /ah:/ phonations were recorded each time the PD subject took the test: four at comfortable level of pitch and loudness, and two at twice the comfortable loudness (elicited with the instruction “twice as loud as the first time”). The signals were sampled at 24 kHz at 16 bit resolution. After initial processing to remove faulty phonations , we processed 4010 phonations for the male subjects, and 1865 phonations for the female subjects.weekly, the actual clinical assessments for motor-UPDRS and total-UPDRS were obtained at trial baseline, three months into the trial, and at six months into the trial. To obtain weekly UPDRS estimates to associate with the phonations we used piecewise linear interpolation going exactly through the measured baseline, three-month and six-month UPDRS assessments average symptom progression in early PD stages (up to about five years) is almost linear in non-medicated patients as observed in clinical metrics classifiers instead of regressorsAlthough the phonations were recorded et al.For further details about the dataset and the AHTD data acquisition hardware, please refer to Tsanas III.digital communications simulation framework to study the distorted signals received through a hostile data transmission channel. The following section describes in detail the process used to simulate the data transmission and reception process of the raw speech signals so that they resemble realistic distorted signals we may expect to have in a practical cellular mobile telephony network.We re-iterate that the aim of the study is to investigate UPDRS estimation using speech signals transmitted over the standard cellular mobile voice telephone network. Given that the data available in the study has been collected using the high quality AHTD equipment we have used a A.one way (simplex) communication; PWP call into an automated voice messaging service and leave sustained vowel phonations. Predictions of symptom severity are extracted from these voice messages and clinical personnel suggest the appropriate course of action offline as a result of the estimated UPDRS. Moreover, the sustained vowel phonations need only be a few seconds long, that is, considerably shorter in duration than most telephone conversations.Creating a realistic simulation of the cellular voice telephony network requires the following steps: (a) encoding the AHTD speech signals into bit-streams for transmission, (b) simulating the transmitter, radio channel, and receiver, and (c) decoding the transmitted bit-streams back into intelligible speech recordings. This application requires only transmitter, the channel , and the receiver. The transmitter aims to assist the receiver to correctly recover the speech signal which may be distorted by the channel. We follow closely the studies of Tsanas et al.B.feature extraction, where we applied speech signal processing algorithms to characterize the phonations and extract characteristic patterns (features), (b) feature selection, where a parsimonious  subset of the originally computed features is selected in order to provide maximally useful information for predicting UPDRS, and (c) feature mapping, where a standard supervised learning algorithm was used to determine a functional form associating the selected feature subset with the clinical outcome (UPDRS). The rationale behind this methodology is that characteristic acoustic patterns in PWP’s voice are indicative of UPDRS. Although confounding factors may affect vocal performance , it is unlikely these contaminate more than a handful of the approximately 6000 recordings used here. We assumed that potential confounding factors do not dominate PWP’s voices to the extent that the extracted dysphonia measures do not provide clinically useful information for estimating UPDRS.We followed three steps to process the recovered phonations and extract clinically useful information: (a) Before characterizing the phonations by extracting dysphonia measures, we removed the vowel onset and offset choosing the three seconds in the middle of the phonation to simplify computational processing. The resulting three second signal was subsequently normalized to facilitate comparisons across recordings.1)et al.https://www.darth-group.com/software). Here, we briefly describe the most important families of dysphonia measures used in this and other studies.We applied the dysphonia measures rigorously defined in Tsanas jitter and shimmerjitter and shimmer variantsRecurrence Period Density Entropy (RPDE) Pitch Period Entropy (PPE) Glottal Quotient (GQ) Some of the most widely used dysphonia measures are Signal to Noise Ratio (SNR)-like quantities. The physiological motivation for this group is that incomplete vocal fold closure leads to the creation of aerodynamic vortices which result in increased acoustic noise. Harmonic to Noise Ratio (HNR) Detrended Fluctuation Analysis (DFA) Glottal to Noise Excitation (GNE) Vocal Fold Excitation Ratio (VFER) Empirical Mode Decomposition Excitation Ratio (EMD-ER) The second group of dysphonia measures characterize Mel Frequency Cepstral Coefficients (MFCC) have been traditionally used in speaker recognition applications, but also appear promising in biomedical speech signal processing contexts Lastly, design matrix of size Overall, we applied 132 dysphonia measures to the speech database, each dysphonia measure producing a single real value per voice sample, resulting in a 2)curse of dimensionality, and arises because adequate population of the feature space requires that the number of voice samples increases exponentially with the number of features feature selection (FS) algorithms are a principled approach to selecting a smaller  feature subset. We refer to Guyon et al.The use of a large number of features (132 in this study) makes it extremely difficult to discern meaningful patterns in the data, and may often be detrimental in the process of mapping the features onto the clinical outcome UPDRS. This problem is known as the Least Absolute Shrinkage and Selection Operator (LASSO) Minimum Redundancy Maximum Relevance (mRMR) RELIEFfeature importance in Random Forests (RF) et al.Here, we compared four FS algorithms: 3)y . That is, we want to obtain a classifier that will use the dysphonia measures to accurately predict UPDRS. There is a large literature on supervised classification, and we refer to Bishop et al.In the preceding steps we have computed 132 characteristic patterns from the sustained vowel phonations, and subsequently applied FS techniques to obtain subsets of those features. Here, we aim to determine the functional relationship 4)As in previous studies Finally, we also trained and assessed the model performance by using a validation scheme leaving samples out from a participant. Specifically, the data from the IV.one standard error rulePrior to any analysis, it is useful to visually appreciate the variability of UPDRS within participants. The methodology was repeated contaminating the speech signals with AWGN or pink noise prior to speech coding and transmission. In both cases, the results were very similar . By comparison, in a recent study in this application where high-quality, high-bandwidth, uncompressed speech signals from the AHTD were used instead, the MAE reported for total-UPDRS was Finally, for the model validation approach where we used the data from V.We had previously demonstrated that using speech signals may be very promising in both (a) differentiating PD subjects from age- and gender-matched healthy controls et al.inter-rater variability (difference in UPDRS score between two expert clinicians), which is about 4–5 points In Tsanas diagnosis. However, all three research teams essentially agree that standard leave-subject-out methods underfit the data when it comes to tracking and endorse the use of validation methods where samples from the same subject are used in both training and testing sets. In particular, Varoquaux recommends only using samples from the subject’s past to estimate future entries in this tracking setting The topic of the appropriate methodology towards reporting out-of-sample performance is considerably more subtle than it first appears and has attracted some recent attention et al. enrolled 168 PD participants and focused on replicating motor-UPDRS using sustained vowels /ah/, a diadochokinetic task, and a reading task  In a related earlier study, Bayestehtashk Concurring with previous findings, we have found that a parsimonious speech feature subset actually improves the out-of-sample MAE, and is also more amenable to interpretation The UPDRS scores used as the response variable in our investigations have different class membership, i.e. this is an unbalanced multi-class classification statistical learning setting, which is known to be challenging in practice. There are different strategies to cope with the class unbalance problem including (a) using different weights internally in the classifier for the samples belonging to different classes , and (b) using different probabilistic cut-offs for the different classes . We stress that these adaptive thresholds should only use information from the training dataset . We have explored both approaches to train different RF models, however neither led to improving the out of sample performance (detailed results not shown). There is a more sophisticated approach to tackle class unbalance in statistical learning, by generating new  data points, e.g. using techniques such as the Synthetic Minority Over-sampling Technique (SMOTE) within each FS algorithm, and the use of different FS algorithms provides insight into FS consistency across FS algorithms. The non-classical dysphonia measures  to identify features which are jointly most predictive of UPDRS. The use of perturbed versions of the data enables the investigation of consistency entclass1pt{minimaMFCCs have been widely used in speech applications and have been previously shown to perform very well in related biomedical applications, e.g. et al.et al.et al.http://www.kayelemetrics.com/) program includes “Voice Turbulence Index”, which is an alternative dysphonia measure relying on the SNR concept, where the spectral energy above 2.8 kHz is used to denote the high frequency energy component in the speech signal We had previously reported that the VFER family of dysphonia measures is amongst the best approaches to quantify information in speech signals to estimate UPDRS for males One very interesting new finding in this study is that UPDRS estimation in males deteriorates considerably more compared to UPDRS estimation in females as a result of the lower quality speech signals. This may be related to the bandwidth restriction, but may also be a consequence of the finite bit allocation available to reproducing the pitch period with pitch pulses. It could also be due to the increased noise that is masked by the formants in the perceptually-weighted linear prediction: this noise may not be heard, but may, nonetheless, be important in PD.The future of health telemonitoring is linked to the potential of smartphones and associated apps. A promising development in that direction would be the deployment of a smartphone app that can record high-quality (wide-band and low-distortion) speech signals. This further underlines the generalization potential of using speech signals towards future PD symptom monitoring systems. Nevertheless, there are still many people  that do not own or do not know how to operate a smartphone. Although it is conceivable this might change in the next 10–20 years as smartphones are becoming more affordable and the current generation of 50–60 year-old people are generally better adapted to the use of smartphones, we envisage the proposed technology here with standard mobile telephony may remain pertinent because of its simplicity in use.Our findings confirm the established view in the clinical speech community suggesting that speech signals of at least 20 kHz should be preferred in clinical applications because there is useful information in the higher frequencies of the spectrum We stress that the results reported in this study were obtained in a simulated digital communications framework involving the GSM standard. Additional tests in real-world contexts using actual mobile phones would be required to validate the robustness of the presented methodology. For example, in practice the channel may or may not always introduce additive white Gaussian noise, although this is generally the assumption in the digital communication literature It is not straightforward to test the proposed methodology in practice: this would involve building the receiver block and ideally testing (a) several types of commercially available microphones and analogue-to-digital conversion hardware, and also (b) the reception of signals in various realistic scenarios , which would probably introduce additional distortion to the transmitted signal. Other scenarios to test include cell handover. Development engineers would need to test the proposed methodology in such diverse practical settings in future work. As we reported recently through a systematic review, there are relatively few paradigms where research findings are translated into digital health interventions to benefit patients The research area of speech signal processing and PD has generated considerable interest in the scientific community in the last 10–15 years and has led to some recent exciting developments. For example, there has been consistent interest in the binary differentiation of PD from healthy controls Telemonitoring in healthcare has received considerable attention lately, but global adoption is always constrained by the prohibitive costs associated with specialized telemonitoring hardware or equipment. Indicative recent explorative applications in the PD domain include the mPower study using iPhones to record a series of motor and cognitive tasks


Research in this area can be broadly divided into those techniques that monitor structural changes in tissues  and those that detect molecular disease activity (positron emission tomography (PET), optical and optoacoustic imaging). The former techniques have largely evolved from experience in human joint imaging and have been refined for small animal use. Some of the latter tools, such as optical imaging, have been developed in preclinical models and may have translational benefit in the future for patient stratification and for monitoring disease progression and response to treatment. In this narrative review we describe these methodologies and discuss the benefits to animal research, understanding OA pathogenesis, and in the development of human biomarkers.Preclinical imaging in osteoarthritis is a rapidly growing area with three principal objectives: to provide rapid, sensitive tools to monitor the course of experimental OA longitudinally; to describe the temporal relationship between tissue-specific pathologies over the course of disease; and to use molecular probes to measure disease activity  The relative importance of each of these pathological features to symptomatic disease and cartilage loss is hotly debated in clinical and pre-clinical arenas. The ability to interrogate molecules in specific tissues of the joint by creating conditional knockout mice is likely to help elucidate these issues.Pathological changes in mouse joints following surgical destabilisation are largely determined by histological assessment at multiple levels within the joint and mirror human disease well; demonstrating progressive cartilage degradation, osteophyte formation, modest synovial hypertrophy and late onset spontaneous pain behaviour. Although in vivo (live) and ex vivo (dead), offers adjunctive information that could be transformative in terms of screening genetically modified animals, understanding pathogenesis, and creating tools that could be useful for human disease monitoring. Specifically these include: (i) the development of rapid quantitative measures that circumvent the need for laborious histological processing and scoring in preclinical models; (ii) the development of prospective measures that could be used in live animals to follow the course of disease in an individual animal over time. This would have a significant impact on reduction of animals in research in line with ARRIVE guidelines; (iii) the ability to use disease activity probes that provide real time information on cellular processes associated with disease.Animal imaging, both In addition to the benefits to the preclinical OA community, ultimately such imaging outcomes have clinical utility as biomarkers. The lack of sensitive biomarkers for OA greatly hampers progress in translation. The only widely accepted biomarker for OA is the Kellgren and Lawrence radiographic score, a composite of joint space narrowing and osteophyte formation, measured by plain X-ray. Joint space narrowing as a biomarker is insensitive, with only around 30% of individuals recruited to OA trials showing X-ray progression over a typical trial period, say 2–3 yearsMolecular imaging probes which report on particular disease activities could lead the way towards personalised medicine and stratification in human OA. For example, selective protease-activatable probes would be able to identify individuals who exhibit high levels of protease activity and monitor their response to protease-inhibitor treatments. Such activities may change over the course of disease and shift between different classes of proteases. One could envisage this type of molecular approach being applied to other selective therapies, for instance in stratifying patients more likely to respond to NGF neutralising or anti-inflammatory therapies.In this review, we provide an overview of the currently available joint imaging modalities in mice, separating the review into those modalities that examine structural changes in joint tissues from those that examine molecular and disease activity changes within the joint. Whilst the focus is on murine joint imaging, we also describe methodologies in other rodents where we believe translation to mouse is realisable.Several imaging techniques have been deployed to study structural outcome measures in disease . Some ofin vivo and ex vivo imaging modalities in orthopaedic research. The mineral calcium in bone absorbs the X-rays and by rotating either the specimen or the X-ray source and detector, 3D data of the bone is reconstructed from multiple projections at multiple angles around the specimenex vivo nanoCT scans of down to 50–600 nm per voxel are possible, allowing clear visualisation of minute features like osteocyte lacunae and vascular canals within a trabeculaIn vivo microCT scans are of lower resolution, in the 4.5–50 μm per voxel range, as it needs to balance motion artefact and the radiation dosage per scan. Oversampling with image binning overcomes motion artefact caused by heartbeats and respiration, but this increases the radiation exposure. In vivo CT allows the same animal to be followed throughout the study. Apart from reducing the number of animals required, this provides greater insight into the temporal development of structural disease, such as the increase in new bone (osteophytes) after surgical destabilisation of the medial meniscus (DMM) (Computer tomography (CT) is one of the most widely used us (DMM) .Fig. 1Pr,Parameters that are typically assessed from CT scans in experimental OA include subchondral bone sclerosis and osteophyte size . Osteoph,in vivo utility can be broadened by adjusting the time of image acquisition after delivery, route of contrast agent delivery (intra-articular vs systemic) and dose  utilises a strong electromagnet to generate a changing magnetic field at a frequency close to the natural frequency of hydrogen atoms. This allows hydrated tissues to be visualised well. Theoretically, MR imaging techniques allow optimal detection of several different joint tissues; from articular cartilage, meniscus, subchondral bone to synovium. Murine OA has been examined using a 9.4T preclinical micro-MRI scanner with an isotropic resolution of 0.068 mm/pixel for T2 images and 0.12 mm/pixel for T1 imagesin vivoet al., pathological changes in the joint were assessed over time following rat meniscectomy. This study describes an initial swelling of the articular cartilage, subchondral bone remodelling, then proteoglycan depletion and cartilage erosion over 8 weeks,The T2 relaxation time has also been derived to indicate structural integrity of articular cartilage in larger rodent models by probing free water proton movement inside the collagen-proteoglycan matrix. Indeed, T2 mapping has been used to detect proteoglycan loss and ECM alterations in rat patellar cartilage post hyaluronidase digestion,ex vivo to study the joint surface in vivo use; there being a trade-off between frequency of the ultrasound wave and penetration depth. Specifically it is unable to penetrate bone. Radiofrequency analysis of sonic signals at the bone-cartilage interface might be useful to delineate this functional unit during OA progressionUltrasonography has been used in clinical assessment of hand, hip and knee OA from grading synovitis, to measuring cartilage thickness, damage to the meniscus and assessing the cartilage–bone interface. In preclinical models, B-mode images have been used to assess synovitis in inflammatory arthritisMolecular imaging techniques detect selective molecular activities which can be monitored over the course of disease. Their value lies in the ability to explore pathogenetic mechanisms and validate therapeutic targets in real-time.18F-Fludeoxyglucose (FDG), which is the most commonly used positron emission tomography (PET) tracer, is taken up at higher rates at regions of heightened metabolic activity, e.g., cancer metastases. When used in combination with CT (PET-CT) skeletal localisation can be elucidated. Umemoto and colleagues examined rat ACLT-induced OA using 18F-fluoride PET and observed higher uptake of 18F in the operated knee starting 2 weeks post operation, particularly within the medial compartment64Cu-peptide targeted to the formyl peptide receptor 1, which is up-regulated upon macrophage activationPositron Emission Tomography (PET) detects gamma rays emitted indirectly by positron-emitting radionuclide tracers. 99mtechnetium, 123iodine or 131iodine. Despite being less sensitive than PET, SPECT allows a longer time window for scans due to the longer half-life of tracers, thus allowing longitudinal imaging over days99mTechnetium-methylene diphosphonate radiotracerSingle photon emission computer tomography (SPECT) is generated by use of a gamma-emitting radioisotope e.g., Improvements have been made to the pinhole design and camera design to improve resolution, magnification and detection efficiencyOptical imaging detects light emitted in the visible to near infrared wavelengths. This light may either be from a bioluminescent source, or the longer emission wavelength of a fluorophore excited at a shorter wavelength of light (fluorescence). This makes it more accessible than the traditional PET/SPECT molecular imaging, as no radioactive material needs to be handled. The main drawbacks of optical imaging stem from the natural tendency of the tissues of the body to absorb and scatter light, leading to low spatial resolution and an imaging depth of about 1–1.5 cm.in vivo using reporter mouse lines containing a luciferase gene under the control of a promoter of interest. Whole body optical imaging systems are used to capture the light emitted following injection of the luciferin substrate. The expression of aggrecanGene expression changes can be studied ,Luciferase reporters can also be used in transplanted cell tracking experiments using the same optical imaging systems to demonstrate the presence of exogenous cells in repairing tissues of OA rats following ACLTin vivo optical imaging systems can also track and quantify far red and near infrared fluorescence. Applications include far red expressing reporter genes or conjugation of the fluorophore to a variety of molecules including recombinant proteins, antibodies, peptides, nanoparticles and drugs. In our experience, the sensitivity of detection of far-red fluorescent protein when expressed by cells is about an order of magnitude less than luciferase.Whole body in vivo models, these would potentially make interesting probes to test in OA. Fluorescence imaging of aggrecan content in murine cartilage has been performed ex vivo using octaarginine-labelled with rhodamine, a methodology based on octaarginine's positive chargeThe far-red probe Cy5.5 has been conjugated to an antibody selective for reactive-oxygen damaged type II collagenin vivo non-invasive measurements of tissue angiogenesis and oxygenation levels without contrast agent. Compared with Power Doppler, PA imaging appears more sensitive for in vivo detection of intra-articular tissue damage and angiogenesis. Following DMM in mice, a reduction in oxygen saturation and increase in vascularity correlated with cartilage damage over timel-lysine, has shown good correlation with tissue glycosaminoglycan (GAG) content and is able to distinguish early from late OAPhotoacoustic (PA) imaging, also known as optoacoustic imaging, is a derivative of ultrasonography. Unlike typical ultrasonography, no acoustic transducer is involved. Instead, a non-ionising laser source sends light to the tissues. This light energy is absorbed by the tissue and converted into heat, and it is this heat that drives rapid thermoelastic expansion, which in turns causes ultrasonic acoustic signal to be emitted. Emerging PA imaging exhibits strengths of both optical and sonic imaging, enabling one to probe the optical absorption properties of endogenous haemoglobin in blood vessels relatively deep in the tissue while achieving the spatial resolution of ultrasound. PA imaging can be applied to Multispectral optoacoustic tomography (MSOT) is an advancement on PA and uses multiple wavelengths of light coupled with unmixing algorithms to excite both endogenous and exogenous light absorbing sources. MSOT, in combination with contrast, has been used successfully in inflammatory arthritis models and may have future application in OA imagingin vivo in real time has huge potential both in terms of understanding the chronology of matrix degradation in OA but also as a biomarker for selecting or predicting response to a particular treatment. The probes work by utilising a cleavable peptide sequence, which only fluoresces upon cleavage  and Cathepsins, with the brand names MMPSense and Prosense. Activity of these probes has been described in collagenase-induced OA as well as surgical destabilisation and mechanical injury models of OA. Unsurprisingly, highest signals have been obtained with the more inflammatory models and early in the post-operative periodL or plasmin may be responsible for the later cleavage of Prosense680Probes with different specificities used in tandem may provide such validation. The different activation times of CatK680 compared with Prosense680 in the mechanical loading model suggests that Cathepsin K is activated early, whereas Cathepsin B, S, in vivo protease cascade during disease. The peptide sequence of the activity-based probe may be designed to increase the selectivity for a particular family member over the others. A peptide sequence, identified from a phage display library screen using MMP-13, was modified and used in an anterior cruciate ligament tear (ACLT) and menisectomy rat model and showed increased cleavage 6 and 8 weeks post-surgeryNewer probes with increased specificity have been developed and it is beginning to be possible to elucidate the Development of probes for other proteases implicated in OA, such as the aggrecanases (ADAMTS-4 and ADAMTS-5), may provide earlier detection of OA and may allow stratification of targeted therapies.ex vivo molecular approaches, define the role of each tissue over the course of disease. When measured prospectively, radiography has the ability to monitor disease progression in real time; reducing numbers of animals used and increasing the power of studies. Although contrast enhanced imaging of cartilage, either through microCT or photoacoustic imaging shows promise in vitro, these agents are not yet validated in vivo and the hope of finding a prospective imaging tool that will substitute for histological scoring of mouse joints is not currently within reach. Imaging probably holds more promise for those structural joint features that are less often reported; bone change, synovial vascularity and bone marrow oedema. Prospective imaging of bone remodelling after joint destabilisation is achievable by microCT scanning although caution should be taken not to over-interpret ossification of soft tissues, such as the meniscus, which occurs readily in mice as they age. Our experience is that epiphyseal volume change, the measurement of which can be automated, may be a more clinically relevant outcome measureRadiographic biomarkers in preclinical disease have the ability to help unravel pathogenic processes relevant to human disease and in combination with in vivo. Ultimately, molecular imaging has important clinical translational promise in the search for early diagnostic, therapeutic and prognostic biomarkers.Newer molecular probes are being validated in pre-clinical models and these offer significant potential; from charting the natural history of specific protease activities over the course of disease to validating new therapeutic interventions. Other aspects of disease pathogenesis, such as molecular determinants of pain could be explored using PET/SPECT, although current resolution will likely preclude precise tissue localisation TV and NHL conceived the review. NHL and CW collected data. All authors contributed to the writing of the manuscript and approved the final version.WO2018020262A).TLV and CW have no conflicts of interest to declare. NHL has a pending patent on diiodotyrosine containing contrast agents for use in cartilage imaging (


In Europe cardiovascular disease (CVD) is responsible for 3.9 million deaths (45% of deaths), being ischaemic heart disease, stroke, hypertension (leading to heart failure) the major cause of these CVD related deaths. Periodontitis is also a chronic non-communicable disease (NCD) with a high prevalence, being severe periodontitis, affecting 11.2% of the world’s population, the sixth most common human disease.There is now a significant body of evidence to support independent associations between severe periodontitis and several NCDs, in particular CVD. In 2012 a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. In the last five years important new scientific information has emerged providing important emerging evidence to support these associations.The present review reports the proceedings of the workshop jointly organised by the EFP and the World Heart Federation (WHF), which has updated the existing epidemiological evidence for significant associations between periodontitis and CVD, the mechanistic links and the impact of periodontal therapy on cardiovascular and surrogate outcomes. This review has also focused on the potential risk and complications of periodontal therapy in patients on anti thrombotic therapy and has made recommendations for dentists, physicians and for patients visiting both the dental and medical practices. Non-communicable diseases (NCDs) are rising in prevalence globally in line with an increasingly ageing population, refined diets and sedentary lifestyles. NCDs account for 41 million deaths each year, or 71% of all global deaths . ApproxiThe greatest global NCD burden arises due to cardiovascular disease (CVD), which is responsible for 17.9 million deaths  and 45% of NCD-induced mortality . In EuroIn this consensus report, the term CVD is used as a general term for atherosclerotic diseases, principally coronary heart disease, cerebrovascular disease and peripheral vascular disease. A number of chronic infectious-inflammatory-immune diseases are associated with significantly higher risks of adverse cardiovascular events, including rheumatoid arthritis, psoriasis, systemic lupus erythematosus and periodontitis , consistPeriodontitis is also an NCD with a high prevalence of 45–50% overall, with the most severe form affecting 11.2% of the world’s population, making it the sixth most common human disease . The Glo63In 2012 a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. The consensus report was based upon four technical papers that systematically reviewed the evidence for epidemiological associations between periodontitis and incident CVD , mechani101The present workshop was jointly organised by the EFP and the World Heart Federation (WHF) to include global experts in both periodontal and cardiovascular disciplines and was held in Madrid on 18 and 19 February 2019. Four technical reviews updating the evidence base from the 2012 workshop were prepared and supplemented by additional studies discussed at the workshop. The reviews focussed on epidemiological associations , mechaniWhile this consensus report focuses predominantly on relevant evidence published since the 2012 workshop, there are biological areas that have subsequently come to prominence, and where the underpinning body of evidence was not covered in the 2013 consensus report; hence, certain pre-2012 manuscripts are referenced to ensure the context of these recent studies is clear.What is the effect of statin intake on clinical periodontal outcomes? and section 5: Cardiovascular risks and complications of periodontal therapeutic interventions were not dealt with in the previous workshop; hence, a full appraisal of the scientific evidence was carried out in this consensus meeting.Furthermore, sections 4.3: Finally, following the review of the presented evidence, recommendations for both medical and dental teams, as well as patients and the public, were elaborated.There is evidence from epidemiological studies that periodontitis patients exhibit significant endothelial dysfunction, measured by flow mediated dilation (FMD), arterial stiffness  and a significantly greater thickness of the carotid intima media (cIMT) and elevated arterial calcification scores. There is one imaging study (ATHEROREMO-IVUS study) associating high levels of antibodies against periodontal pathogens and a lower extent of positive atheromatous plaque remodelling .There is robust evidence from epidemiological studies for a positive association between periodontitis and coronary heart disease. A systematic review , which wThere is evidence from epidemiologic studies for a positive association between periodontitis and cerebrovascular disease. A systematic review , which wThere is limited but consistent evidence that individuals with periodontitis have a higher prevalence and incidence of PAD compared to individuals without periodontitis . For cro2Several studies report positive associations between periodontitis and heart failure. There is evidence from a large Asian study using the Taiwanese National Health Insurance Research Database reporting a significantly higher incidence of atrial fibrillation in individuals with periodontal diseases compared to individuals without periodontal diseases  .There is currently limited scientific evidence that CVD is a risk factor for the onset or progression of periodontitis.From three studies investigating the association between periodontitis and secondary cardiovascular events, two large studies did not find a significant association 100; howeThere is evidence that oral bacterial species can enter the circulation and cause bacteremia, which has been demonstrated following daily life activities , although it has been studied more frequently following professional interventions .The risk of bacteremia has been associated with periodontal health status in a systematic review, suggesting a higher risk of bacteremia associated with gingival inflammation . A recenWhilst there are methodological limitations in some of the reported studies, the overall picture supports the contention that bacteremia results from daily life activities and oral interventions, and it is more frequent, of longer duration and involves more virulent bacteria in periodontitis patients.P. gingivalis and A. actinomycetemcomitans in athero-thrombotic tissue when culturing the atheroma samples Thus, there is insufficient evidence to support or refute the potential benefit of the treatment of periodontitis in preventing or delaying ACVD events .Table Moderate evidence suggests periodontal treatment does not have an effect on lipid fractions, whilst there is limited evidence suggesting periodontal treatment reduces arterial blood pressure and stiffness, subclinical ACVD (as assessed by mean carotid Intima-Media-Thickness), and there is insufficient evidence of an effect on ACVD biomarkers of coagulation, endothelial cell activation and oxidative stress.Statins are medications prescribed to decrease LDL cholesterol. Numerous trials have demonstrated their benefit for the prevention of cardiovascular diseases .Interestingly, statins possess various additional properties relevant to the pathogenesis and treatment of periodontitis . In partA systematic review with meta-analysis of pre-clinical in vivo trials reported a positive effect of local or systemic statin administration for the prevention of alveolar bone loss in experimental periodontitis models in rodents .Several observational clinical studies have evaluated the effect of systemic statin intake on periodontal conditions , 123. StVery few clinical studies have been designed to evaluate the effect of adjunctive systemic statin intake in conjunction with periodontal therapy , 36, 1088Non-surgical treatment of periodontitis involving supra- and sub-gingival instrumentation of the affected dentition  is often delivered in several short sessions. Alternatively, full-mouth non-surgical periodontal treatment can be performed within 24 hours.Delivering periodontal treatment in a full-mouth fashion  triggers a one-week acute systemic inflammatory response associated with a transient impairment of endothelial function . This diinvasive dental treatment in elevating ischemic cardiovascular risk ) .invasive dental treatment  is associated with an increased risk of incident acute cardiovascular events  within the first four weeks of treatment recorded.Minassian et al.  performeIn summary, the Group concluded delivering periodontal treatment is safe with regard to cardiovascular risk.invasive dental treatment on the incidence of Ischemic Events in patients with established CVD or after an event.There is limited evidence on the effects of A small RCT on the effects of the treatment of periodontitis on CVD biomarkers in patients with established CVD  showed nIn the PAVE feasibility randomized secondary prevention trial, provision of periodontal scaling and root planing treatment in patients with established CVD did not increase the incidence of cardiovascular events compared to the control group (community treatment) within six months .In summary, the Group concluded delivering periodontal treatment is safe with regards to cardiovascular risk in patients with established CVD.Periodontal treatment consists of numerous procedures with different levels of bleeding risk. However, this risk of bleeding is low in the vast majority of procedures and can be easily controlled with local haemostatic measures.Perioperative bleeding risk varies according to the extent and invasiveness of the periodontal procedure performed. The majority of periodontal procedures may be grouped within the ESC/AHA/EHRA 122. Low Individuals undergoing single acetylsalicylic acid (ASA) therapy (aspirin) in different therapeutic dosages, as well as therapy with clopidogrel, ticlopidine or ticagrelor show no statistically significant differences in frequency of bleeding events when compared to controls  62.Dual antiplatelet therapy, most commonly ASA in combination with clopidogrel, may pose a certain risk for postoperative bleeding complications; however, it appears these haemorrhagic events may be managed safely with local haemostatic measures 85.Thus, current evidence does not support discontinuation of antiplatelet therapy before dental procedures, irrespective of the type of therapy employed  or the type of procedure performed .In patients taking oral anticoagulant therapy  and undergoing dental extraction, minor dental procedures and dental implant placement do not seem to increase the risk of bleeding compared to patients who discontinue oral anticoagulant therapy 139. Ther10Limited trials and evidence are available on the management of patients on novel oral anticoagulant (NOAC) therapy undergoing dental treatment; hence, the Group concluded further studies regarding dental procedures in these patients are strongly encouraged.It appears there is no need for interruption of NOAC therapy in most dental treatments due to a low incidence of bleeding complications, which can be successfully managed with local haemostatic measures when comparing groups continuing NOAC and groups discontinuing NOAC therapy , 92, 137Patients with periodontitis should be advised there is a higher risk for cardiovascular diseases, such as myocardial infarction or stroke, and as such they should actively manage all their cardiovascular risk factors .Patients with periodontitis and a diagnosis of CVD should be informed they may be at higher risk for subsequent CVD complications and, therefore, they should regularly adhere to the recommended dental therapeutic, maintenance and preventive regimes.Collect a careful history to assess for CVD risk factors, such as diabetes, obesity, smoking, hypertension, hyperlipidemia and hyperglycemia. Suggestthe patient consults his/her physician if any of these risk factors are not appropriately controlled.Oral health education should be provided to all patients with periodontitis and a tailored oral hygiene regime, including twice-daily brushing, inter-dental cleaning and in some cases the use of adjunctive chemical plaque control may be appropriate.People presenting with a diagnosis of CVD should receive a thorough oral examination, which embeds a comprehensive periodontal evaluation, including full-mouth probing and bleeding scores.If no periodontitis is diagnosed initially, patients with CVD should be placed on a preventive care regime and monitored regularly (at least once a year) for changes in periodontal status.In people with CVD, if periodontitis is diagnosed, they should be managed as soon as their cardiovascular status permits.Irrespective of the level of CVD or specific medication, non-surgical periodontal therapy should be provided, preferably in several 30–45 minute sessions to minimize a spike of acute systemic inflammationSurgical periodontal and implant therapy, when indicated, should be provided in a similar manner as in patients without CVD.However, attention should be paid to:Hypertension. It is recommended to measure the patients’ blood pressure (after appropriate relaxation) before the surgical intervention, and in cases of high blood pressure (above 180/100 according to expert opinion), the surgery should be postponed until the patient’s blood pressure is stabilized.Medication with antiplatelet and anticoagulant drugs. Because periodontal and implant surgical procedures usually impart only a low to medium risk of bleeding in general terms, the dentist should not change a patient’s medication or in cases of doubt he/she should consult the physician/cardiologist prior to the surgical intervention. Consideration should also be given to the local management of bleeding complications that may arise.Current AHA/ACC/SCAI/ACS/ADA/ESC/ACCP guidelines on perioperative management of antithrombotic therapy do not suggest discontinuation of anti-platelet therapy for Low Bleeding Risk procedures , 43, 57.Various approaches for perioperative management of anticoagulant therapy have been suggested. The Group reviewed the guidelines on perioperative management of vitamin K antagonists (VKA) and suggests discontinuation of medication treatment if the INR is 4 or below for Low or Medium Bleeding Risk procedures . However57After reviewing novel anticoagulant (non VKA) and direct anticoagulant (NOAC/DOAC) therapies guidelines, the Group concluded that for Low Bleeding Risk periodontal procedures no discontinuation of anticoagulants is recommended 122. ThesLastly, in cases of combined anti-platelet and anticoagulant therapies, which pertain to patients with the highest thrombotic and ischemic risk , when periodontal procedures (either of Low or Medium Bleeding Risk) are required, any alterations in medication should be discussed and agreed upon with the responsible medical professional 122. In eIn cases of triple therapy  or one anticoagulant plus one anti-platelet, such patients need individualised management by the responsible medical professional according to their thrombotic and haemorrhagic risk .It is important to highlight that local haemostatic agents  should be used and dental clinicians should consider the confounding effect of local anaesthetic with vasoconstrictors.Patients with a risk of endocarditis should be premedicated with antibiotics following current guidelines (such as the European or the American guidelines).People with cardiovascular disease who have extensive tooth loss should be encouraged to pursue dental rehabilitation to restore adequate mastication for proper nutrition.European Society of Cardiology  [People without a diagnosis of CVD but with risk factors for CVD should be informed about their CVD risk and referred to a physician for appropriate risk assessment, diagnostic testing and follow-up care. For oral health professionals, risk assessment may be performed based upon the recommendations of the , SCORE) .Because of the potential negative impact of periodontitis on CVD complications, the following recommendations are made:Patients with CVD should be advised periodontitis may have a negative impact on CVD and may also increase the risk of CVD events.Patients should be advised effective periodontal therapy may have a positive impact upon CVhealth.For people with CVD, physicians should ask about a prior diagnosis of periodontitis. If a positive diagnosis has been made, the physician should seek to ascertain that appropriate periodontal care and maintenance are being provided.Patients with CVD should be asked about any signs and symptoms of periodontitis, including bleeding gums during brushing or eating, loose teeth, spacing or spreading/drifting of the teeth, oral malodor and/or abscesses of the gums or gingival suppuration.If a positive history is elicited, then a prompt periodontal evaluation should be recommended before their scheduled annual check-up.In the case of a negative history, people with CVD should be advised to check for the above symptoms, and if a positive sign appears, they should visit their dentist at least once per year.For all patients with newly diagnosed CVD, referral for a periodontal examination should occur as part of their ongoing management of CVD. Even if no periodontitis is diagnosed initially, an annual oral/dental check-up is recommended.The physician should liaise with the dental surgeon over periodontitis management in CVD patients on anticoagulant/antiplatelet therapy prior to the oral intervention and/or periodontal surgery to avoid excess bleeding or the risk of ischaemic events.People with CVD must be aware that gum disease is a chronic condition, which may aggravate their CVD, and requires lifelong attention and professional care.There is a need to clean the teeth and gums very carefully at home. Personalized advice will be provided by the oral health professional.This may includeTwice-daily brushing with either a manual or electric toothbrush;Cleaning between teeth using inter-dental brushes where they fit; where they do not fit, then flossing may be useful;Use of specific dentifrices and/or mouth rinses with proven activity against dental plaque, if advised by oral health professionals;If left untreated, gum disease can lead to tooth loss and may also make CVD preventive measures harder to control;Gum disease may be present and deteriorate with no apparent symptoms, so the dentist should advise their patient that even without current gum disease, they should still receive regular dental check-ups as part of managing their CVD.Dentists should be able to identify the early signs of gum disease, but patients should also suspect gum disease if noticingRed or swollen gums;Bleeding from the gums or blood in the sink after tooth brushing;Foul taste;Longer looking teeth;Loose teeth;Increasing spaces between teeth/teeth moving apart;Calculus (tartar) on teeth.Patients should inform their dentist about the outcome of their visits to the physician and provide an update on their CVD history and any changes in medications. Patients should inform the dentist if they are on anticoagulant therapy.Patients should understand it is important to keep their mouth and whole body as healthy as possible with regular dental and medical visits.If your physician has told you that you have cardiovascular disease (CVD), you should make an appointment with a dental surgeon to have your mouth and gums checked.This is because people with CVD may have a higher chance of getting further complications when they have gum disease. The earlier you seek help, the better the outcome will be.You may have gum disease if you have ever noticedRed or swollen gums;Bleeding from your gums or blood in the sink after you brush your teeth;Foul taste;Longer looking teeth;Loose teeth;Increasing spaces between your teeth, or your teeth drifting apart;Calculus (tartar) on your teeth.If you have noticed any of these problems, it is important to see a dentist as soon as possible.Gum disease may also be present and get worse with no apparent that you have it, especially if you smoke, so even if you do not think you have gum disease now, you should still have annual check-ups of your mouth as part of managing your CVD. Your dentist will be able to pick up early signs of gum disease.You need to clean your teeth and gums twice daily at home for a minimum of two minutes. Also, cleaning between your teeth daily is important, and your oral health professional will show you how to do this. You should visit a dental surgeon as soon as possible for a diagnosis and advice on what you need to do. It is important to keep your mouth as healthy as possible with regular oral and dental care, according to the recommendations of your oral health professional.The additional file for this article can be found as follows:10.5334/gh.400.s1Supplementary Appendix 1.Antithrombotic therapy: when, how and why. Comprehensive approach for oral health professionals.


Pancreatic imagingDuring the last decades, diagnostic radiology in general and abdominal imaging in particular have gone through substantial changes and developments. Hereby, a shift of paradigm could be observed from mere diagnostic assessment of pathological disorders to the evaluation (and even prediction) of therapeutic success based on imaging parameters. Furthermore, a quantitative tissue analysis of different organs based on multi-parametric imaging has become feasible. At the European Congress of Radiology (ECR) 2020, the latest research in abdominal imaging was presented in a total of seven scientific sessions. This editorial does not aim to give an all-encompassing summary of all scientific lectures. Rather, a subjective selection of highlights is presented with a focus on three main topics of abdominal imaging including (a) pancreatic imaging, (b) prediction of therapeutic success based on imaging features and (c) advances in order to optimize and shorten imaging protocols.Pancreatic cystic lesions (PCL) as incidental findings play a huge role in the daily clinical practice. Although the majority of these lesions only has a low risk of malignant transformation, there are several aspects that remain unsolved including (a) if and when endoscopic or surgical intervention is needed, (b) worrisome imaging features of cystic lesions that may be considered markers for an increased risk of malignancy and (c) the time interval for imaging surveillance of patients with cystic pancreatic lesions. Zhu et al evaluated MR morphologic features as well as clinical data predicting the progression of PCL . More thBoraschi et al performed a study in a similar context . They ai(b)Prediction of therapeutic success based on imaging featuresThese studies carry several messages I believe to be important: cystic pancreatic lesions only show a slow increase in size and therefore are suitable for imaging surveillance. Only a minority of patients has yet to undergo surgery. However, radiologists should be aware of risk factors that may lead to a change of the surveillance rate. These factors include patients’ age, number of lesions, presence of septa and visible communication with the pancreatic duct.One of the most challenging questions particularly in the setting of cancer imaging remains the prediction of therapy success for different therapeutic strategies. Wei et al utilized gadoxetic acid-enhanced MRI in order to identify preoperative imaging biomarkers for the prediction of tumor recurrence in patients with HCC . A totalOverall, these trials underline the great potential of multiparametric imaging in tumor patients with vast clinical consequences. Imaging features may help to answer the question whether a specific treatment may be successful or if other alternatives should be taken into consideration. Furthermore, it may be a guideline to tailor surveillance strategies: if pretherapeutic imaging reveals high risk of tumor recurrence, time intervals for follow-up imaging need to be adapted. Despite these promising results, there are still several open questions. One challenge is related to the practicability of these strategies. What soft- and hardware is needed and how time-consuming is data evaluation? Furthermore, a large variety of studies have been performed so far at different centers using different imaging modalities and different imaging parameters. Hence, it would be advantageous to synchronize results in order to allow for a more uniform implementation.(c)Advances in order to optimize and shorten imaging protocolsAll-encompassing MR examinations of the abdomen are often time consuming due to the large number of sequences that are acquired. Examination slots yet are limited and valuable. Thus, one may wonder whether we really need to perform extended MRI examinations all the time or if it is possible to use shortened protocols that are adapted to the clinical situation. This may be particularly interesting when high risk patients undergo screening procedures. Pecorelli et al focused on this issue analyzing patients with liver cirrhosis or chronic hepatitis B, who have an increased risk for the development of hepatocellular carcinoma (HCC) . An MRI A similar study was performed by Willemssen et al . They exThe evaluation of short MRI protocols is promising and will encourage radiologists to tailor examinations to the clinical circumstances. Hence, a dedicated first time MRI exam of the liver could encompass more or different sequences than a follow-up exam or a surveillance exam of patients with a high-risk profile. If we follow this strategy, examination time can be spared and more exams per time unit could be performed. However, there are still some problems to be solved, e.g., when to use i.v. contrast. Furthermore, the proposals for short MRI protocols are somewhat heterogeneous. It will be the task of expert groups or multi-center trials to overcome this limitation in the future.


Moving to a continuing care retirement community (CCRC) and living apart together (LAT) as a repartnering form, represent new late-life beginnings. A larger qualitative study on LAT relationships constructed in the CCRC identified envy and jealousy yet they were not examined in-depth. Envy is wanting something we lack whereas jealousy is fear of losing something that is ours to another. These emotions are rarely explored in the context of older adults’ relationships. Our aim is to examine experiences of envy and jealousy from perspectives of residents aged 79 to 96 and staff, heuristically using Goffman’s framework on (semi)-totalitarian institutions. 30 semi structured qualitative interviews were conducted in three CCRCs in Israel with 10 LAT residents, 10 residents not LAT, and 10 CCRC staff members including social workers. Analysis was conducted based on principles of thematic analysis and triangulation. Findings refer to kinds of envy, ignoring envy, and the development and consequences of jealousy and/or envy related to LAT in the CCRC. Conclusions address how semi-totalitarian CCRC features influence envy and jealousy experiences including implications for assisting social workers, older adults and their family members to adjust to life in the CCRC and assist CCRC management and staff to address possible consequences of envy and jealousy.


Traumatic aortic dissection is most commonly caused following sudden deceleration injury. It most commonly involves descending thoracic aorta (DTA) and is associated with high mortality and morbidity if not treated urgently. Confirmation of diagnosis often requires contrast-enhanced computed tomography (CECT) or magnetic resonance imaging (MRI), which is time consuming, expensive, and often not available at many health-care facility. Transesophageal echocardiography (TEE) is equally efficient to CECT and MRI in diagnosing aortic dissection. It may also provide additional information that can be very useful for the management of the patient. In some cases, the likelihood of error in the diagnosis of such a critical condition with normal cardiovascular variations is expected. Herein, we describe a case with primary diagnosis of aortic dissection that led to final diagnosis of an aortic shelf that medically managed with a good long-term prognosis. In patients suspected to aortic dissection due to any cause, the specialized evaluation using the most accurate and sensitive tools is strongly recommended to discriminate normal vascular variations from major vascular defects requiring emergent surgical interventions. Several diagnostic tools have been recently developed to early detection of aortic dissection including ultrasonography, computed tomography, and magnetic resonance imaging.2 However, despite high precision of such diagnostic tools to detect aortic dissection, in some cases, the likelihood of error in the diagnosis of such critical condition with other cardiovascular benign or even normal variations that requires only medication or elective managements, not surgical endovascular interventions is expected.3 One of these variations is aortic shelf as a rare congenital variation in aorta that placed in differential diagnosis with aortic dissection, but with a completely different prognosis as well as different treatment approach.4 Herein, we describe a case with primary diagnosis of aortic dissection that led to final diagnosis of an aortic shelf that medically managed and led to a good long-term prognosis.Traumatic aortic dissection is most commonly caused following sudden deceleration injury. It most commonly involves descending thoracic aorta (DTA) and is associated with high mortality and morbidity if not treated urgently. Confirmation of diagnosis often requires contrast-enhanced computed tomography (CECT) or magnetic resonance imaging (MRI), which is time consuming, expensive, and often not available at many health-care facility. Transesophageal echocardiography (TEE) is equally efficient to CECT and MRI in diagnosing aortic dissection. It may also provide additional information that can be very useful for the management of the patient.A 50-year smoker man who referred to emergency department due to multiple trauma caused by car accident was initially managed. In chest X-ray, fracture in the posterior arch of left side seventh to ninth chest ribs , bilateral pleural effusion and left side pneumothorax were revealed that managed by left side chest tube insertion. Bed side FAST was also considered detecting any abnormal finding. In laboratory test, there was no evidence in decreased hemoglobin level. The patient had a stable hemodynamic status. Chest CT scan revealed a periaortic hypo-dense area proximal to descending aorta suggesting hematoma and also a possible feature of dissection flap suggesting a traumatic descending aortic dissection. In emergent transthoracic echocardiography on the first day of admission, a localized dilatation with a dimension (16*18 mm) in medial side of proximal descending aorta was found, but there was not turbulent flow or evident FLAP attributable to aortic dissection. In CT angiography of the aorta , a vertiUnfortunately, the presence of natural aortic shelf as a normal variation may be misleading to professionals interpreting it as a life-threatening condition such as aortic dissection. This misdiagnosis may be even to the wrong treatment approach. In this regard, using a combination of imaging modalities to achieve a true definitive diagnosis  is advisable.6 But in some cases, aortic shelf may be an evidence of cardiovascular anomalies needing repairing interventions early in life. For instance, imaging the coarctation of the aorta may be led to appearing a posterior aortic shelf commonly in fetus but rarely in adulthood.7 In other word, the coarctation of the aorta in adults may appear as a localized posterior shelf-like thickening of the aortic wall. Although, most of these abnormalities are diagnosed as vascular anomalies needing surgical repairing approaches, in most cases, vascular shelf especially in aorta may be considered only as a normal variation without any evidence of hemodynamic abnormalities or further life-threatening events. In the case presented here, the diagnosed was primarily focused aortic dissection due to precedent trauma but the absence of turbulent flow or evident FLAP strongly raised the suspicion of this diagnosis. In this regard and by using more accurate diagnostic modality including CT angiography and esophageal echocardiography, the diagnosis of aortic dissection was completely ruled out. Thus, the patient was finally monitored and followed-up for a six-month period showing reducing clinical manifestations without any long-term complications. So in patients suspected to have localized aortic dissection at proximal DAO due to any cause without strong clinical evidences, the specialized evaluations using the most accurate and sensitive tools is strongly recommended to discriminate normal vascular variations from major vascular defects requiring emergent surgical interventions.In the region of the ductus arteriosus an anterior or medial shelf may normally exist just proximal to the aortic origin of the ductus. It is important not to mistake this for a typical posterior coarctation shelf. In addition, the size of the transverse arch must also be noted as it invariably is somewhat small, particularly in the newborn with severe coarctation.None declared.None.


As they mention, several small trials of RV outflow or RV septal pacing versus RV apical pacing have shown somewhat conflicting results, with most studies indicating a shorter QRS duration with RV nonapical pacing but failing to show a clinical benefit. However, statistical power has been lacking, as only two of these trials contained more than 100 patients. In addition, there is a lack of standardization for RV septal and RV outflow lead placement positions, and it is not always completely clear to which endocardial surface a lead may be attached. With this in mind, Worsnick et al.’s discussion of methods for obtaining a true septal lead position is valuable for anyone unfamiliar with the technique.It is in this setting that Worsnick et al. review alternatives to RV apical pacing in this issue of Perhaps most interesting is the discussion of His-bundle pacing by respected authors in this field. The excitement surrounding His-bundle pacing across the electrophysiology community is growing, particularly on social media (#dontdisthehis). Randomized data for His-bundle pacing are currently lacking, but at least two randomized trials are ongoing (NCT02805465 and NCT02700425) with expected completion in 2018 and 2021, respectively. Furthermore, nonrandomized studies have suggested that His-bundle pacing gives significant benefits over RV apical pacing and is a reasonable substitute for CRT (including for resynchronization of left bundle branch block). However, whenever nonrandomized data are reported, there is an inherent publication bias toward positive results. Further considerations regarding His-bundle pacing include more complex device programming (which requires a deep understanding from every person who is likely to interrogate or reprogram the device) as well as the unknown effects of a long-term  His-bundle lead position and the inevitable extraction of these leads.Despite these concerns, the likely benefits of His-bundle pacing are great enough that the adoption of this technique will continue to expand. This growth will likely be bolstered by improved tools, such as deflectable His-bundle delivery catheters or catheters of various shapes (such as is seen with coronary angiography). Therefore, as with many other rapidly evolving procedural techniques, trial data may underestimate future benefits due to limitations of the technology available at the time of enrollment.While we expect to see an escalation in His-bundle pacing over time, we also expect an increase in leadless pacing options and fully subcutaneous defibrillators. It remains to be identified how these three technologies will interface with one another, though the His-bundle region does not seem to be well-suited to currently available leadless pacing systems due to the lack of trabeculations. Therefore, while the immediate future of His-bundle pacing seems poised to leap forward with small changes in the delivery system, the more distant future of pacing in general is not currently clear at this time.


Junco hyemalis, we found that SA exhibited different patterns of association with RTE depending on the overall temperature regime and on precipitation. While thermoregulatory function predicts larger SA at higher RTE, we found this only when the RTE existed in an environmental context that opposed it: atypically cold minimum temperature in a warm climate, or atypically warm maximum temperature in a cool climate. When environmental context amplified the RTE, we found a negative relationship between SA and RTE. We also found that the strength of associations between SA and RTE increased with precipitation. Our results suggest that trait responses to environmental variation may qualitatively differ depending on the overall environmental context, and that environmental change that extremifies already-extreme environments may produce responses that cannot be predicted from observations in less-extreme contexts.Species increasingly face environmental extremes. Morphological responses to changes in average environmental conditions are well documented, but responses to environmental extremes remain poorly understood. We used museum specimens to investigate relationships between a thermoregulatory morphological trait, bird bill surface area (SA) and a measure of short-term relative temperature extremity (RTE), which quantifies the degree that temperature maxima or minima diverge from the 5-year norm. Using a widespread, generalist species,  NaturalThe avian bill is shaped by dietary , communiJunco hyemalis) in California, USA, over a 50-year time period. We predicted that, in accordance with thermoregulatory pressures as posited by Allen's Rule, bill surface area would be positively related to short-term relative temperature extremity (relative minimum and maximum temperatures). We further predicted that these relationships would be modulated by environmental context in the form of the absolute temperature regime and precipitation (as a proxy for humidity), expecting that the relationship with relative minimum temperature would be stronger at colder absolute temperatures, the relationship with relative maximum temperature stronger at warmer absolute temperatures, and both relationships stronger at higher levels of precipitation.Responses of bill surface area to climate at shorter time scales, which could capture brief but extreme environmental fluctuations, remain comparatively unexamined. Here, we develop a measure of relative temperature that quantifies the extremity of temperature within the context of a location's usual thermal regime. This relative measure accounts for the possibility that the impact of environmental variation on an organism may depend not only upon the absolute value of that variation, but also upon its value in comparison to the baseline conditions usually experienced by that organism . Any mea2.2.1.2; )Our results add to growing evidence that the effects of environmental extremes are not simply linear extensions of the effects of more moderate environmental variation and can be qualitatively different ,11,48. T