Baran et al.) that can lead to better translational approaches in different animal welfare and scientific areas as described below.Novel and emerging technologies, such as home cage monitoring (HCM) systems, permit 24/7 collection of behavioral data under undisturbed conditions. HCM minimizes the impact of stressors that arises from human interaction or the testing in novel test environments, which may bias readout parameters (science) and/or affect animal welfare since science and welfare are highly interdependent. There is increasing evidence that laboratory animals living under enriched and group-housed conditions display a behavioral repertoire that is much richer as compared to what is observed in classical behavioral experiments . Behavioral phenotyping experiments performed by classical tests show limited replicability due to idiosyncratic results to a particular laboratory  and Europe (https://www.cost.eu/actions/CA20135/) that now try to harmonize the definitions of HCM, provide examples, generate guidelines and try to identify standards for improved comparability of results and new developments.HCM occurs in a cage where the animal spends more than a limited period of time (≥24 h) to either perform certain behavioral tasks or display physiological responses. However, proper HCM should be differentiated from benchtop technologies as highlighted by Richter suggests that controlled heterogenization in combination with HCM may lead to increase constructive and predictive validity. Along the line of data reproducibility, Engelbeen et al. tried to replicate findings in the mdx mouse model of Duchenne muscular dystrophy by testing mice in a standard battery of behavioral tests using both conventional and HCM methods. In contrast to previous findings using only female mdx mice, a learning deficit could not be reproduced suggesting an interaction of genetic and environmental factors contributing to cognitive performance differences in mdx mice.The reproducibility crisis in animal research is a well-known issue , interpretation of large, unstructured data sets up to IT/cybersecurity issues. This means that not only scientists are necessary in a successful implementation of HCM systems.According to Baran et al. and in the review by Grieco et al. These articles provide an overview of the use of video monitoring, the interpretation of data generated, and the scope that can be obtained from an expanded use of video monitoring technology. More recent developments advancing this technique are explained by Gharagozloo et al. who show that complex and more naturalistic behaviors can be studied through machine learning approaches and artificial intelligence.Behavioral video monitoring has a long history as shown by Voikar and Gaburro, other technologies are applied in substance use disorders as described by Iman et al. Specifically, RFID-based technology to recognize event-based animal behavior can be employed. Such technology allows interpretations in the context of reward learning and more complex behaviors such as sociability. The use of RFID transponders in group-housed mice also allows to study lifetime changes in animal behaviors in normal and pathological conditions which may address important scientific questions such as the interaction between cognition and aging Kahnau et al. which is fundamental especially in neurodegenerative disease progression.Alternatives to video monitoring with specific applications to learning and memory are described by Wassermann et al. A follow-up study from the same group by Zentrich et al. used spontaneous activity as marker of animal welfare. Here, an acute experimental colitis mouse model, starting from the highest level of severity as established by a clinical score (10 different parameters), expressed a reduction in locomotion that remained significantly suppressed until the mice recovered from the treatment indicating that HCM can be used for routine severity assessment in biomedical research.Four articles address the connection between animal welfare and behavioral experimental outcome. This includes using behavioral outcome to classify the severity level of a treatment in the context of animal welfare. In fact, simple routine operation such as cage-change can increase physiological parameters  for 90 min up to a few hours  vs. bottom rack position (lower light intensity). For cage position from left to right there was still a 3-fold difference in light intensity. This suggests that for increased uniformity and reproducibility of cage rack studies, each cage should have its own controllable light source. Interestingly, animals in red tinted cages, which block most visible light, did not display such cage variation in activity between cage locations. However, they showed a reduced diurnal activity level as compared to animals in standard transparent cages. This shows trade-offs between positive aspects for animals vs. care takers and visual daily checks.The effect of ambient illumination on the behavior of animals has not been systematically studied in the animal facility where animals are bred and kept. Yet, it is well known that light conditions can dramatically affect the expression of various behaviors in visual behavior tests. Therefore, Moore and Brook used HCM-derived activity to assess the effect of replacing an individual companion female by a different one on spontaneous locomotion of males in their cage. Using such technology revealed that replacing a female resulted in an increase in activity for up to 4 h. This was followed by a compensatory reduction in activity during the subsequent dark phase as potential sign of fatigue. A resulting refinement suggestion is that cage mate replacements should occur toward the end of the light-phase when animal activity increases, probably impacting less on the normal circadian activity.Golini et al.Despite differences in their clinical manifestations, neurodegenerative diseases such as Alzheimer, Parkinson and others share common symptoms both at the clinical and at the preclinical level. An example are alterations in resting bouts in a model of Amyotrophic lateral sclerosis (ALS). Here, resting bouts were used as an index of reduced sleep to establish a novel biomarker called rest disruption index (RDI). The RDI indicates the reduction of sleep in SOD1G93A mice at 16–18 weeks of age. This finding correlates with symptoms in typical behavioral tests such as the grid test as described by van Heusden et al. Only 6-month-old transgenic APP/PS1 mice displayed an increase in the number of consecutive incorrect responses. The F8M approach indicates the possibility to monitor performance repeatedly over months. However, the expected cognitive decline was not detected as early as expected, since an earlier study  was used to test transgenic APPswe/PSEN1dE9 (APP/PS1) mice in the delayed alternation task to gain water as reward in a longitudinal manner from 2–6 months of age by Wooden et al. the researchers substantially improved the object recognition test by applying an inexpensive 3-step approach that allows to adjust the experimental conditions according to the model for providing more robust results.Visual and olfactory cues are typically very difficult to be analyzed within HMC systems. In one of the very first articles of our Research Topic Caglayan et al. used olfactory stimuli to investigate learning set acquisition. Full automation in this context eliminated human interaction and permitted individualized training schedules where a specific mouse could enter to the next level of training based on individual performance. This successfully allowed investigating higher-order cognitive function in the home cage.Advanced testing procedures in the learning, memory, and cognitive domain are based on single animal performance in an operant chamber. When an operant chamber is connected to the home cage, a form of behavioral enrichment is achieved that simultaneously allows 24/7 voluntary testing of RFID-tagged mice. This approach of Caglayan et al. used a home cage connected with a gating mechanism to the operant chamber to perform the stop-signal-task for assessing symptoms of attention deficit disorders and schizophrenia. The automated HCM approach required only minimal experimenter involvement, reduced training time for the mice by about 20%, and importantly, considerably improved task sensitivity.In their second study, Schuessler et al. customized an experimental chamber consisting of a safe nest and a foraging area with an operant lever, food port, water spout and shock grid floor. Foot shock was delivered specifically in the area where food and water were available. Using this “Risky Closed Economy” approach, fear and anxiety-related behavior were studied nearly 24/7 for extended periods as described, indicating flexibility based on decision-making when and how much to forage. This is a more naturalistic foraging scenario under controlled threat condition. Similarly, RFID-chipped transgenic mice in a partially automated HCM can be studied for their social, cognitive behavior in a complex environment that helps researchers identify the gene x environment interactions for affective and cognitive consequences of psychiatric disease as shown by Volkmann et al..Fear and anxiety are commonly studied with short experiments that cannot be applied repeatedly, and therefore, do not allow the analysis of disease progression or the assessment of long-term treatment. via transient occlusion of the middle cerebral artery and are behaviorally characterized through standard motor tests. However, repetition of such tests might lead to habituation and changes in performance. Therefore, researchers tried to identify hallmarks after stroke induction on locomotor activity in HCM. A new open-source tracking software allowed calculating distance traveled, speed and also turning behavior since stroke models have the tendency to move more unilaterally if untreated. Here, recovery from stroke was not augmented by dietary induction as shown previously in humans by Shenk et al. A follow-up paper from the same group determined whether voluntary wheel running in the HCM would induce a faster recovery from stroke. In fact, stroke-induced mice with running wheel had a better recovery from stroke in terms of motor skills as well as increased functional connectivity, cerebral blood flow, and vascular quality as reported by Lohkamp et al..Most stroke models in rodents are induced HCM also served in the evaluation of mice exposed to SARS-CoV-2. K18-hACE2 transgenic mice, harboring the humanized angiotensin-converting enzyme 2 (ACE2) receptor to which the spike protein binds, were used to assess the pathophysiology induced by SARS-Cov-2. Typically, in infectious disease studies using mice both viral titer and body weight are monitored. However, SARS-Cov-2 infections in humans cause fatigue rather than body weight loss. Using a HCM system, K18-hACE2 transgenic mice infected with SARS-CoV-2 were evaluated daily for body weight as well as locomotor activity see . These rKönig et al. indicated significant effects of strain, gender and circadian phase on voluntary physical activity and energy expenditure in automated HCM. This study highlights that naturally occurring genetic variation modulates various innate activity behaviors, food intake and energy expenditure in mouse strains.A survey of 30 mouse strains by Frostig et al. aimed to examine the organization of infant exploration in a novel setting. Here, the stationary mother serves as “home-base” reference point to characterize the exploration patterns of typically developing infants, but does not serve, or serves much less as a reference, for non-typically developing infants. This approach identified profound differences between typically and non-typically developing human infants with respect to their excursions from the mother as important reference point. Thus, this approach may serve as novel assay to screen for deviating child development with very early diagnostic potential at 8–18 months, as observed in autism spectrum disorder, if replicated and extended on a larger scale.An intriguing development originates from phenotyping studies of predominantly mouse behavior based on the long-standing collaboration between Ilan Golani and Yoav Benjamini .SG works as scientific director at Tecniplast S.p.A. ML works as Chief Executive Officer at Sylics BV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Inguinal hernia repair using surgical mesh is a very common surgical operation. Currently, there is no consensus on the best technique for mesh fixation. We conducted an overview of existing systematic reviews (SRs) of randomised controlled trials to compare the risk of chronic pain and recurrence following open and laparoscopic inguinal hernia repairs using various mesh fixation techniques.We searched major electronic databases in April 2020 and assessed the methodological quality of identified reviews using the AMSTAR-2 tool.We identified 20 SRs of variable quality assessing suture, self-gripping, glue, and mechanical fixation. Across reviews, the risk of chronic pain after open mesh repair was lower with glue fixation than with suture and comparable between self-gripping and suture. Incidence of chronic pain was lower with glue fixation than with mechanical fixation in laparoscopic repairs. There were no significant differences in recurrence rates between fixation techniques in open and laparoscopic mesh repairs, although fewer recurrences were reported with suture. Many reviews reported wide confidence intervals around summary estimates. Despite no clear evidence of differences among techniques, two network meta-analyses (one assessing open repairs and one laparoscopic repairs) ranked glue fixation as the best treatment for reducing pain and suture for reducing the risk of recurrence.Glue fixation may be effective in reducing the incidence of chronic pain without increasing the risk of recurrence. Future research should consider both the effectiveness and cost-effectiveness of fixation techniques alongside the type of mesh and the size and location of the hernia defect. Abdominal wall hernia is a common clinical manifestation in general surgery, with a prevalence of 4% for people over 45 years of age and 1.7% for all ages. . While mInguinal hernia repair ranks among the most performed surgical procedure in general surgery, with up to 80,000 procedures per year in the UK alone, and over 20 million procedures worldwide , 4. Up tToday, the treatment of choice is hernia repair involving the placement of a mesh performed either through open or laparoscopic surgery. The use of mesh varies worldwide from 0 to 5% in low-resource countries to 95% in high-resource countries . Mesh reThe incidence of moderate to severe chronic groin pain following inguinal mesh repair is reported to be around 10%–12% , 10 It iSeveral randomised controlled trials (RCTs) and systematic reviews have compared various mesh fixation methods in both open and laparoscopic surgical procedures to assess clinical outcomes such as recurrence, post-operative infection, the incidence of chronic groin pain, and time-to-recovery. However, overall evidence in support of any specific fixation method has been conflicting. Furthermore, no attempt has been made to summarise the body of evidence from published systematic reviews –18. IdenOverviews of systematic reviews are a relatively novel methodology, which offers the advantage to summarise different interventions for the same condition or clinical population where several systematic reviews already exist . ConsideThis overview aimed to summarise the evidence from existing published systematic reviews on the benefits and risks of mesh fixation techniques for open and laparoscopic inguinal hernia repairs in adults.The methods of this overview were pre-specified in a research protocol according to the recommendations outlined in the Cochrane Handbook of Systematic Reviews of Interventions  and the Study designs: systematic reviews and/or meta-analyses of RCTs.Participants: adults with unilateral or bilateral inguinal hernia who underwent an open or laparoscopic mesh repair;Intervention: methods for mesh fixation ;Comparator: any comparator intervention investigated;Outcome measures: chronic groin pain and recurrence.Where a systematic review included both RCTs and non-RCTs, we included and analysed only the subset of randomised studies.We included published systematic reviews of randomised controlled trials (RCTs), which focused on mesh fixation techniques for the repair of inguinal hernia and met the following inclusion criteria:To identify eligible reviews published in English, we searched major electronic databases,  in April 2020. We used both MeSH and text search terms  and combined them appropriately with the Boolean connectors, “AND” and “OR”. We did not apply any restriction in terms of publication date. In addition, we perused the reference lists of identified systematic reviews for any further relevant references.Two researchers (AA and NH) independently screened the results of the searches and selected articles based on their title and abstract with disagreement being resolved by discussion or consultation with a third reviewer (screening phase). Articles that appeared to be potentially relevant were retrieved in full and analysed by the same two reviewers in line with the pre-specified inclusion criteria. For each included review, data were extracted by one author (AA) using a form developed and piloted for this overview. Information on the following items was recorded: administrative details and scope of the review, review characteristics, number of RCTs, characteristics and number of participants, characteristics of interventions and comparators, outcome measures (recurrence and chronic groin pain), and review results. For systematic reviews that included a meta-analysis (MA) or a network meta-analysis (NMA), quantitative effect measures, including confidence intervals (CI) or credible Intervals (CrI), were recorded.The quality of the included systematic reviews was assessed by one reviewer using the validated AMSTAR-2 (A Measurement Tool to Assess systematic Reviews-2), which comprises 16 items.  As well We summarised the main characteristic of each review  and synthesised data on outcomes of interest (chronic pain and recurrence rate) using summary tables . We did n = 1), full-text articles not available  (n = 9), no access to the full-text article (n = 1). The PRISMA flow chart summarising the study selection process is shown in Fig. The initial search retrieved 136 records. After the removal of duplicates, 108 abstracts were screened for eligibility. After full-text assessment of 32 potentially relevant articles, 20 systematic reviews  met the inclusion criteria and were included in the overview. Twelve reviews were excluded as they did not meet the pre-specified inclusion criteria. The main reason for exclusion were non-English publications  and 4 of these combined the results of the included RCTs in a meta-analysis. Results of these reviews were consistent in showing a lower incidence of chronic pain after glue fixation than after mechanical fixation, although effect sizes varied between reviews . , 36, 37 Table Overall, most reviews showed no significant difference in recurrence rates between different mesh fixation techniques regardless of whether open or laparoscopic surgery was used.In both open and laparoscopic inguinal hernia repairs, several techniques for mesh fixation have been studied in the attempt to keep the mesh in the appropriate position whilst reducing the pain experienced by patients after surgery and limiting the incidence of recurrence. A consensus regarding which technique is optimal has yet to be reached and, at present, the decision about which to use is often based on the surgeon’s preference. This overview examined evidence from 20 systematic reviews (one Cochrane systematic review and 19 non-Cochrane reviews) assessing methods for mesh fixation during both open and laparoscopic surgical approaches.Regarding the rate of chronic pain after open mesh repair for inguinal hernia, the results of this overview show a consistent pattern in favour of glue fixation compared with suture fixation, whereas there was no clear indication of a significant difference between the self-gripping method and sutures. It is worth noting that the systematic review by Rausa et al.  was the With regards to laparoscopic mesh repairs, due to the low number of studies available for each repair method, most reviews did not report results separately for TEPP and TAPP approaches or perform relevant sensitivity analyses. The results of this overview show that, in general, glue fixation (four systematic reviews) had a lower rate of chronic pain compared to mechanical fixation (tack and/or staple). The recent network meta-analysis by Techapongsatorn et al., assessed 11 RCTs and found no significant difference between various types of mesh fixation for laparoscopic hernia repair ; however, glue was ranked the best for reducing chronic pain compared to suture and glue and suture were ranked the highest for lowering the incidence of recurrence compared to mechanical fixation. Little information was available from the identified systematic reviews to assess glue fixation versus self-gripping mesh.In general, there is an indication that non-penetrating methods of mesh fixation such as glue fixation have a reduced risk of chronic pain compared to mechanical fixation and suture. This is in line with the notion that techniques, which can reduce tissue trauma and nerve injuries, are likely to reduce the risk of chronic pain. On the other hand, suture appears to increase the risk of chronic pain and there was only limited evidence that this could lower the risk of recurrence. While there is still a lack of robust evidence to support the routine use of glue fixation in open and laparoscopic hernia repairs, it may be effective in reducing chronic pain without increasing the risk of recurrence and, therefore, can be regarded as a suitable alternative to mechanical fixation or suture.There are some limitations to the present overview. There were considerable differences in the inclusion and exclusion criteria among the included systematic reviews, such as the type of hernia , age of participants, and the duration of follow-up. In some systematic reviews, evidence was restricted to a small number of trials  or to a single trial.There was also a considerable disparity across existing reviews in terms of the type of fixation techniques that were compared, and, in the way, postoperative pain was defined and measured. This was the consequence of the fact that all reviews included a pool of heterogeneous trials with mixed characteristics. For example, various types of glue , mechanical fixation methods  and sutures (absorbable and non-absorbable), as well as various types of mesh  were used across included studies. This hampered the comparability of the studies included in each review and therefore the reliability of the overall review findings. There was also a lack of clear subgroup analyses within the identified reviews, which could have been useful to investigate the heterogeneity between included studies. Almost all reviews reported outcomes (chronic pain and recurrence) within 12 months with only one systematic review reporting recurrence rates at 5 years . TherefoWhilst some of the existing reviews recognised that some fixation techniques are more expensive than others , none properly assessed the cost-effectiveness of routine use of the different techniques for mesh fixation in clinical practice. This overview focused exclusively on evidence published in full in English; we cannot exclude the likelihood of having missed some relevant publications available in other languages. We used the AMSTAR-2 tool to assess the method of the included systematic reviews , but we In conclusion, based on the results of the existing systematic reviews there is an indication that glue fixation may be more effective than other techniques in reducing the rate of chronic pain presenting up to 1 year postoperatively without increasing the risk of recurrence. However, current systematic reviews of RCTs assessing methods for mesh fixation after open or laparoscopic inguinal hernia repair have a variable degree of quality and considerable heterogeneity. We believe that there is no need for further systematic reviews on this clinical topic unless new RCTs are published or new techniques are developed. Future research should consider various methods of mesh fixation alongside the type of mesh , the size and location of the hernia defect as well as the type of surgical approach chosen. There is a clear need for a uniform definition and assessment of postoperative pain in patients who undergo inguinal hernia repair as well as a need to fully understand the impact of different fixation techniques on clinical outcomes. To inform clinical practice and improve the burden that chronic pain and risk of recurrence pose to a significant number of patients, future research should assess longer-term outcomes (> 1 year), including patient’s quality of life, as well as the cost-effectiveness of different fixation techniques. It is worth noting that recurrent surgery is technically much more difficult than primary surgery and with higher risks of complications (including chronic pain). Therefore, establishing the optimal treatment of a primary inguinal hernia procedure to reduce recurrences would be extremely important to move hernia surgery forward.


Long-believed inevitable with age, urinary incontinence (UI) --like dementia – has proved neither ineluctable nor untreatable. Moreover, older adults remain continent despite abnormal lower urinary tract (LUT) function! The key is that the LUT is just one risk factor, and incontinence results from contributors at every level: from drugs and diseases beyond the LUT, to problems of brain and physical function, to multiple issues within the LUT itself. Such insights have provided the rationale for a nontraditional diagnostic and therapeutic strategy, one that has not only improved outcomes but also enabled creation of previously-believed heretical approaches that address the LUT last and only if necessary. In addition, this approach enabled development of Medicare’s Minimum Data Set for frail elderly and, more importantly, may facilitate development of scalable ways to raise the floor of care for other geriatric syndromes as well.


This second volume of the Research Topic provides an up-to-date picture on how humans control balance and body motion during daily motor tasks, with a special focus on the relationship between postural adjustments, body balance and motor performance in healthy adults and individuals with various health conditions. It includes 18 contributions separated into four sections, each of them focusing on a specific aspect of balance and body motion control. In the first section, the focus is on multisensory integration in balance control during standing, sitting and gait initiation. The second section reports results of studies investigating the adaptability of gait and balance control under specific and controlled conditions in healthy individuals. The third section reports results of studies focusing on gait and balance disorders in specific clinical populations. Finally, in the last section, results of studies focusing on the development of innovative tools and methods to assess and improve gait, balance and cognitive functions in neurological patients are reported.Balance control is a complex motor skill which involves the integration of many types of sensory information  and can be modified by sensory input alterations consequent to a pathology or aging processes.Sozzi et al. by using spectral analysis of center-of-pressure (COP) oscillations and different sensory conditions. While standing on foam, vision did not reduce low-frequency oscillations, while touch diminished the entire spectrum, except for the medium-high frequencies, as if sway reduction by touch would rely on rapid balance corrections.Postural instability during stance with eyes closed was investigated by Desgagnés et al. showed that surface anodal stimulation over the right mastoid in seated participants induced an ipsilateral body sway. Current intensity and duration affected amplitude and occurrence of the inhibitory short-latency and the excitatory medium-latency responses in lumbar erector spinae muscles; responses were amplified by right, but not left, head rotation. Vision did not influence the responses, suggesting its minimal contribution to vestibulomotor control during sitting. The lack of response reversal in the sagittal plane may reflect the biomechanical role of lumbar erector spinae to tune the lumbar lordosis during an induced body sway.Lauzier et al. and Kimijanová et al. According to the Canadian group, feet soles vibration and standing on foam increased COP parameters, but foam was more effective than vibration in both groups. Conversely to foam, changes in COP parameters after vibration were no longer different between groups when correcting for the baseline levels; thus aging seems to differently affect “motor” and “sensory” components, the latter being relatively unaltered. The Slovak group showed instead that young people significantly modified anticipatory postural adjustments (APAs) during gait initiation when a previous vibratory perturbation was delivered to lower leg muscles. Sensitively scaled APAs according to the actual position of the body verticality, an effect which is absent in old participants. Significant age-related declines in APAs were observed regardless of altered proprioception. This seems to indicate that at the transition from standing to walking they probably require higher reliance on the visual input.Relative contribution of sensory and motor components on postural control in young and old participants was investigated both by Perucca et al. presented normative data of SOT for 80–84 and 85–89 years groups and concluded that the vestibular balance tended to be affected by aging more than vision and proprioception-based systems. However, Moon et al. stressed that SOT has limitations  that hinder its use in clinical practice. Thus they developed an innovative system, called VR-ComBAT , that provides a safe, feasible, and cost-effective virtual reality environment allowing the investigation of multisensory integration in balance control.Since aging is known to increase the falling risk, the Sensory Organization Test (SOT) applied to old people appears to be a useful tool for assessing postural stability, risk of falling, and balance improvement during rehabilitation. Bertrand-Charrette et al. pointed out that pain experimentally induced by electrical stimulation caused robust gait pattern adaptations in healthy participants and thus provided a valid model to study musculoskeletal pain-induced gait adaptations under controlled conditions.Investigating gait and postural control adaptations under specific and controlled conditions in healthy individuals can be a relevant approach to identify solutions for the assessment and improvement of these functions in people with balance and mobility impairments. De Pieri et al. showed that healthy adults generate a larger support moment during the stance phase to maintain the knee stable compared to normal walking. These results suggest that the support moment can be an insightful parameter for assessing the muscle demand associated with gait in patients affected by toe walking, such as patients with cerebral palsy or idiopathic toe walking.During toe walking Tebbache and Hamaoui showed that during a sit-to-stand task, an increase in backrest inclination resulted in an increase in the activity level of the neck and trunk flexor muscles during the postural phase (prior to seat-off), but a decreased level activity of some lower limb muscles during the rising phase. These results, which reveal a change in muscle demand as a function of backrest inclination, may be particularly useful in developing solutions to improve sit-to-stand performance in people with muscle weakness.Several musculoskeletal and neurological conditions can affect gait and postural control often leading to increased disability and significant reduction in quality of life and life expectancy. Consequently, much attention has been given to the investigation of both gait and postural control in patients with various neuromusculoskeletal conditions, either to establish baseline comparisons with healthy individuals, track natural history of diseases or assess clinical improvement following clinical interventions. As illustrated by the following studies, translational research including basic sciences, applied research and pragmatic clinical studies significantly contributes to the development of tailored rehabilitation strategies targeting gait and balance disorder.Student et al. compared mean sway amplitude and mean velocity of both the COP and COM in patients with early-to-mid stage Parkinson's disease (PD), aged-matched healthy individuals and young healthy adults. Using a moving room paradigm, the authors showed that the net effect of a visual perturbation on mean COP velocity was significantly higher in patients with early-to-mid stage PD and aged-matched healthy individuals suggesting that such changes are mostly an effect of aging rather than a specific effect of early PD.Xia et al. showed several differences between stroke patients and healthy participants. Among the several between group differences observed, the authors reported changes in anticipatory muscle activations in the extensor carpi radialis muscle as well as changes in APAs.In a study investigating the task specificities of anticipatory muscle activations throughout various hand activities in subacute stroke survivors, Houle et al. summarized the best currently available scientific evidence regarding walking capacity in patients with lumbar spinal stenosis and associated neurogenic claudication. Their review showed on one side that several physical and psychological factors are associated with walking capacity in patients with lumbar spinal stenosis, and on the other side that assessment of walking capacity and associated physical and psychological factors lacks standardization therefore limiting stronger conclusions on the topic.Walking capacity is a critical health outcome in several patient populations with musculoskeletal or neurological diseases. Through a scoping review, Liu et al. evaluated lower limb proprioception in 80 patients to assess the association between proprioception and clinical features of spinocerebellar ataxia type 3. Their results showed that lower limb proprioception was significantly impaired in patients with spinocerebellar ataxia type 3 and that increased impairment was associated with increasing age at onset and increasing disease duration.Spinocerebellar ataxia type 3 is a neurodegenerative disorder characterized by progressive ataxia, external progressive ophthalmoplegia, and other neurological manifestations. Souza et al. compared the index finger kinematics during a free-endpoint whole-body reaching task and a cup-to-mouth task in participants with traumatic brachial plexus injury (uninjured limb) and healthy matched controls. Significant differences in movement parameters led the author to suggest that traumatic brachial plexus injuries lead to increased motor planning cost for the movement of the uninjured limb and that this cost is higher in tasks that require greater postural balance.Finally, The development of innovative tools and methods directed to assess and improve gait, balance and cognitive functions in PD patients and stroke are important for rehabilitation interventions.Bhatt et al. developed a computer game-based rehabilitation treadmill platform for dual-task (DT) assessment and training in PD. Authors showed that this platform has the ability to repeatedly record reliable DT interference effects over time and track PD progression. The platform is directly applicable to other diseases than PD that affect gait and cognition.Delafontaine et al. reported that bilateral applications of FES to the tibialis anterior muscles (ankle dorsi-flexor) may improve the capacity of PD to generate the APAs associated with gait initiation. Future studies are required before considering that this tool is valuable to optimize the effects of L-DOPA medication on gait initiation.Functional electrical stimulation (FES) and robot-aided stretching device are two other promising tools that may improve balance and gait function in neurological patients. Zhai et al. stressed that stroke survivors with impaired control of the ankle due to stiff plantar-flexors often experience abnormal postural control, which affects balance and gait. These authors reported that robot-aided and manual ankle stretching training provided similar improvements in the ankle properties and balance post-stroke. However, only the robot-aided stretching training improved spasticity and stiffness of dorsiflexion significantly. Authors thus suggested that robot-aided rehabilitation may optimize current rehabilitation programs in stroke survivors.Zhang et al. defended the point-of-view that the practice of tai chi, a traditional Chinese martial art, can improve balance ability and reduce the risk of falls in people with mild to moderate PD.Beside the use of innovative tools, physical activity is important for the rehabilitation and promotion of healthy aging. In conclusion, this collection contributes to a better understanding of the basic mechanisms underlying the control of body balance and body motion during daily motor tasks. The collection also promotes the development of innovative tools and methods to assess and train gait and balance, with relevant applications in the fields of neurodegenerative conditions and rehabilitation.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Zhang et al. summarized the possible pathways in a schematic figure, which provided a framework for researchers to follow when one would like to investigate the impact of local anesthetics on cancer behaviors and associated mechanisms. Generally speaking, local anesthetics involve activating the death signaling and inhibiting survival pathways. According to the current results, their roles seem not independent, more likely to be modulating the chemotherapy during cancer treatment. Furthermore, Zhang et al. pointed out some of the solutions and research priorities, such as standardization of experimental methods, investigation of the stemness of the cancer cells, identification of the specific tumors or types of the cancer cells that may be particularly sensitive to certain local anesthetics, as well as the use of bioinformatics. From the viewpoint of residual cancer cells, Wall and Buggy specifically looked into the effect of lidocaine perioperatively, which has a well-established role either while being infused intravenously or in the provision of epidural anesthesia. Their review provided a state-of-the-art summary of recent advances regarding perioperative lidocaine and its in-depth biological effects from possible aspects. Based on a schematic overview of the pathophysiological mechanisms involved in perioperative metastasis formation, they explained potential tumor-related mechanisms of action of systemic lidocaine during surgery by a model of colonic tumor excision. Although published dosage guidelines may aid in ensuring safe practice, the appropriateness of intravenous lidocaine has recently been questioned in terms of its impact on cancer behavior given as yet inconclusive benefits. Both review articles mentioned that the drug concentrations in most animal and cell experiments were significantly higher than in clinical use. Given the considerable degree of biological heterogeneity between different malignancies, it would be difficult to extrapolate the result of one cancer to another. Different anesthetics promote or inhibit metastasis, depending on the type of tumor cell as well as the type, dose, and regimen of anesthetics used.In two review articles, the mechanisms of cancer inhibition by local anesthetics were reviewed in detail. Liu et al. found that sevoflurane, though with increased migration of 4T1 breast cancer cells, has no difference compared with isoflurane and desflurane on the growth and lung metastasis in the mouse residual tumor model. Chamaraux-Tran et al. provided a prototypical model of combining metabolomics and onco-anesthesia to evaluate the impact of anesthetic on metabolites in triple-negative breast cancer cell lines. Especially for female cancers, ferroptosis might be an emerging target to assess the impact of anesthetics on cancer behavior. Both Zhao et al. and Sun et al. explored anesthetic-specific ferroptosis-related signaling pathways in vitro with or without chemotherapeutic agents. In the two retrospective propensity score matching study investigating ovarian cancer surgery Tseng et al. found propofol-based total intravenous anesthesia is associated with better survival compared with desflurane anesthesia, and Zhang et al. reported a positive effect of intravenous infusion of lidocaine on short-term outcomes and survival. However, robust prospective clinical evidence supporting the beneficial anti-cancer effect of intravenous lidocaine treatment is lacking. The scarcity of randomized controlled trials on this topic is also in line with the conclusion made by Luo et al. in this Research Topic. Using the bibliometric method Luo et al. found that the research hot spot in the influence of anesthesia on tumor prognosis mainly focused on retrospective studies over the past 20 years, and the direction is likely in a gradual transition from retrospective studies to prospective randomized controlled trials. Shi et al. conducted a prospective randomized controlled trial comparing propofol-based general anesthesia with local anesthesia in patients with hepatocellular carcinoma undergoing radiofrequency ablation. It would be interesting to know that even propofol-based general anesthesia would aggravate cancer behavior and precipitate pro-inflammatory cytokine secretion from the viewpoint of the patient’s serum. Shi et al. speculated that physiological changes during general anesthesia or accompanying opioid usage during propofol-based anesthesia might be responsible for the results. However, another randomized trial directly evaluating early recurrence by Li et al. showed no difference between paravertebral-propofol-based regional anesthesia and sevoflurane-opioid-based general anesthesia for breast cancer surgery. A trend of reduced recurrence hazard under regional anesthesia in estrogen receptor-negative group, though not significant, warrants an even larger sample to clarify the influence in this high-risk group.This Research Topic also includes some specific analyses, including tumor-specific, anesthetic technique-specific, and anesthetic agent-specific publications to elucidate the association and possibly causal relationship. Most publications on this Research Topic involved female cancers. in vitro studies evaluating the effects of lidocaine or other local anesthetics, the drug was usually incubated with cultured cells for some time, but such a period of stable and direct drug exposure cannot be possible for an in vivo experiment when local anesthetics were locally injected unless it is given into the body compartment that would achieve a constant systemic concentration or where local anesthetic can directly expose themselves to the target tumor. Therefore, what we called clinically relevant concentrations would be serum concentration achieved by intravenous (<20 μM) or epidural lidocaine infusion (around 1 μM). Other situations with higher concentrations cannot be called clinically relevant concentrations unless they are administered into specific body cavities, such as intra-bladder or intra-abdominal injection for direct drug exposure. The difficulty in translating the higher concentration results to the clinical setting  comes from unstable lidocaine exposure to the tumor since the highly soluble lidocaine hydrochloride can be cleared out in vivo quickly with rather limited duration. Otherwise, to retain lidocaine at the injection site much longer, lidocaine nanoparticles proposed by Yang et al. can significantly slow down the release rate of lidocaine and could be one of the solutions to help translate the results from higher concentrations studied in the web bench and make it more adequately compatible with the model of local injection around solid tumors. It would be even better if future publications could comment on the effects of lidocaine on cancer behaviors based on clinically relevant concentrations and stratified by body compartments administered, respectively, to help readers evaluate its true impact without being confused by describing the effects according to the results from mixed concentration scales (mM vs μM).In many Although all of the above articles described the inhibitory effects of local anesthetics on cancer behaviors, a balanced report cannot be achieved without including the possible aggravating effects of intravenous lidocaine infusion on cancer behaviors. The biphasic effect, especially from drugs, is not uncommon in clinical practice from our previous experience . It mighZhang et al., experimental model wise, we call for further studies using clinically relevant concentration (<20 μM) to evaluate the impact of lidocaine on cancer behaviors to mimic stable circulatory lidocaine exposure to the tumors during intravenous or epidural infusion. Cancer stem cell and mechanisms associated with cancer stemness, such as epithelial-mesenchymal transition, would be the future research hotspot in this field. Network analysis using ingenuity pathway analysis corresponding to specific cancer settings might be a practical tool to systematically predict gene alteration according to the wet bench results following lidocaine exposure as a solution to meet the direction toward bioinformatics.From describe above and meanwhile to meet the future directions pointed out by


Osmanthus, and Camellias), imported woody ornamental plants have become dominant on the Chinese horticulture market. It should be noted that, in this study, we exclude any woody ornamental plants found on the market without accurate ancestral and/or breeding information, such as many azaleas on the Chinese market  for the production of woody ornamentals, with a value of 8051 million EUR . Despitee market . In conte market .Most existing frameworks for breeding of woody ornamental plants have focused on creation of new morphological variations, like classical/traditional cross breeding and artificial polyploidization . CurrentIt is well recognized that natural hybridization occurs frequently in >25% of known plant species  and playWhether these natural hybrids are a stable, long-term phenomenon or a relatively recent occurrence, certain hybrid genotypes will have been selected out because of genetic incompatibilities and other reasons  seem to have been detectable with adequate morphological data alone  to which natural hybrids may belong  CharAlthough in the genomic era, integration of the genomic technologies (e.g. GWAS associated trait selection) for ornamental woods with availability of whole-genome information will enhance selection efficiency, we are confident that our framework can provide a reference and be beneficial to colleagues, particularly those working toward breeding new cultivars of most woody ornamental plants without whole-genome information and establishment of genetic transformation systems. Several new cultivars of Chinese indigenous plants generated according to our proposed framework will be emerging in the near future, and we hope that some of them will be commercially competitive against the imported cultivars on the Chinese flower market even before the successful application of genome editing in woody ornamental plants in China.


Current medical physics graduate training in the United States seldom explicitly includes education on foundational skills necessary to produce Patient-Centered Care (PCC)-focused healthcare providers. Such abilities include effective communication, critical reflection, and ethical decision-making. In this article, we present examples of curricula used to purposefully introduce these skills into graduate training to fill this gap. Presented didactic activities include an introduction to patient communication, ethics in medical physics, and a primer in health disparities for medical physicists. Although development of new curricula is resource-intensive when left to individual programs, we here propose resource-sharing and interprofessional collaboration to overcome these barriers. Patient-Centered Care (PCC), also referred to as Patient and Family-Engaged Care (PFEC), has gained popularity in recent years as it has been shown to improve patient satisfaction and may contribute to better outcomes, including a reduction in racial and ethnic disparities in health care quality We will give a brief overview of three curricula, at different stages of implementation, that introduce effective communication, critical reflection skills, and ethical decision-making to medical physics graduate students through learning about patient communication, ethics, and health disparities. A table summarizing the characteristics of these educational activities  can be found as a supplemental material.An introductory curriculum for effective patient communication strategies was developed at Virginia Commonwealth University by an interdisciplinary group consisting of a medical physicist, a radiation oncologist, and social workers. We summarize the design and outcomes here, but further details can be found elsewhere This training was designed for graduate students following experiential learning theory principles Fourteen participants (8 from VCU and 6 from Duke) completed this program, and their patient interaction scores, as determined by the standardized patients, increased from a median of 70 % to 88 % . Self-evThe basic bioethics principles that have been widely adopted in the field of medical physics  are, by definition, patient-centered. We will discuss three teaching tools that are rooted in patient-centered principles and that facilitate this type of critical thinking: (1) case-based learning, (2) interactive eLearning, and (3) timely topical engagement. All three can be incorporated into existing medical physics graduate programs, regardless of whether they offer bioethics training in a dedicated course, as part of a seminar series, or other formats.Case studies afford students the opportunity to engage with real-world ethical dilemmas using patient-centered ethical principles as a foundation. The use of case studies in ethics education is not a new idea; however, many of the cases available for use in ethics training are broad in their focus and not specific to medical physics. The AAPM’s Working Group on Ethics Case StudiesIncorporating interactive eLearning modules into ethics and professionalism training facilitates active learning , responds to the shift in how the current generation of digitally native students learns, and allows curriculum to be shared easily between programs, potentially elevating the ethical, patient-centered practice level of all medical physics students Finally, ethics curriculum should include engagement with timely topics oriented toward the future of the medical physics field. Two examples of timely topics include the changing role of the medical physicist and dilemmas arising from the use of artificial intelligence (AI) in medicine The training briefly presented here is the first health disparities (HD) training geared towards medical physicists, to the authors’ knowledge. This curriculum was developed at Virginia Commonwealth University through collaboration between a health disparities scholar and a medical physicist. It was designed following transformative learning theory We have presented here a few examples of curricula that can be implemented at the graduate level to introduce future medical physicists to formalized training promoting effective communication, ethical decision-making, and critical reflection skills. Mastering these talents lays the foundation for patient-centered care practices and provides more holistic training for a profession that is increasingly reliant not only on technical knowledge but also on interpersonal abilities. In a recent study, it was shown that physics consults with patients undergoing radiotherapy reduced anxiety and increased patient satisfaction Implementing these programs is not without challenge. Finding room to fit new material into an already dense curriculum is difficult, and it can become an impossible request if it requires programs to create didactic activities from the ground up. Using short but effective educational activities to introduce these materials, such as the course units presented here, can logistically facilitate the inclusion of these topics. Additionally, practice of these skills could be integrated into other areas already existent in traditional medical physics curricula to provide students with opportunities to practice and further develop these abilities throughout their graduate education. For example, the application of these skills could be embedded into assignments in diagnostic and therapy physics courses, clinical rotations, seminar series, etc and could be made an integral part of research project design and dissemination. Moreover, resource-sharing  could be used amongst medical physics graduate programs to avoid burdening each individual institution with the creation of new trainings. This approach has previously been successfully used to implement trainings in radiation oncology The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Funding for the Patient Communication training was provided by Virginia Commonwealth University School of Medicine for VCU students and from Duke University Graduate School for Duke students. Funding for the eLearning project was provided by the University of Nebraska Medical Center Office of Academic Affairs eLearning funded awards program.


Heterogeneity is a complex feature of cells and tissues with many interacting components. Depending on the nature of the research context, interacting features of cellular, drug response, genetic, molecular, spatial, temporal, and vascular heterogeneity may be present. We describe the various forms of heterogeneity with examples of their interactions and how they play a role in affecting cellular phenotype and drug responses in breast cancer. While cellular heterogeneity may be the most widely described and invoked, many forms of heterogeneity are evident within the tumor microenvironment and affect responses to the endocrine and cytotoxic drugs widely used in standard clinical care. Drug response heterogeneity is a critical determinant of clinical response and curative potential and also is multifaceted when encountered. The interactive nature of some forms of heterogeneity is readily apparent. For example, the process of metastasis has the properties of both temporal and spatial heterogeneity within the host, whereas each individual metastatic deposit may exhibit cellular, genetic, molecular, and vascular heterogeneity. This review describes the many forms of heterogeneity, their integrated activities, and offers some insights into how heterogeneity may be understood and studied in the future. Endocrine resistance is a major clinical problem for the treatment of hormone-receptor (HR+) positive breast cancer (BC). HR+ tumors comprise the most prevalent molecular subtype, representing over 70% of all newly diagnosed breast cancers each year. However, using endocrine monotherapies to improve the overall survival (OS) rates for patients with HR+ breast cancer has shown only modest further increases since the introduction of tamoxifen in the early 1970s. As monotherapies, only Fulvestrant has shown an ability to increase OS; aromatase inhibitors confer no OS benefit relative to tamoxifen . Adding Endocrine therapies that target the activation state of estrogen receptor-α  fall into two broadly defined agent classes – antiestrogens and aromatase inhibitors. Antiestrogens act primarily by competing with endogenous 17β-estradiol and other estrogens for binding to ER and blocking its activation. Tamoxifen and structurally related triphenylethylene-like compounds are mostly partial agonists and often described as selective estrogen receptor modulators (SERMs). The ER antagonist properties of tamoxifen are evident in its ability to reduce the risk of breast cancer mortality by almost one-third . FulvestTwo ligand independent actions can alter ER function – mutation or phosphorylation of specific residues. ER can be phosphorylated at multiple residues, with serine-167 (S-167) and serine-118 (S-118) in the AF1 region of the ER protein being the most prevalent . Higher 1, or exiting to the G0, phase of the cell cycle. Cell death occurs more slowly. Both changes are observed in endocrine sensitive, HR+ experimental models and in many HR+ breast tumors in patients. For example, in endocrine treated breast tumors reduced proliferation is evident from the drop in expression of the Ki67 proliferation marker  in the tumor microenvironment (TME) that are often ER-negative and likely not killed by endocrine therapies. While cellular heterogeneity can be one determinant of responsiveness to any given therapy, heterogeneity is complex and multifaceted.Breast tumors and their associated microenvironments are often described as being highly heterogeneous. Generally, this is taken to reflect cellular heterogeneity, although the precise nature of the heterogeneity invoked may not be defined explicitly. Cellular heterogeneity usually refers to the presence of different cell types within the TME and exhibits both spatial and temporal variability within an individual tumor and among different colonized sites in the same patient (primary tumor and distant metastatic sites). While tumor cells may remodel some features of their microenvironment to create a supportive niche at a site distant from the primary tumor, the microenvironment of each metastasis will reflect, to some degree, the normal tissue in which it resides. In breast cancer, common metastatic sites include bone, brain, lung, lymph nodes, skin, and viscera. Location in the body creates one form of spatial heterogeneity  cells. As definitively normal cells, their genome sequence profiles would be expected to be similar. However, each of these cell types has a different phenotype and function and will also express different transcriptome, proteome, metabolome and epigenome profiles (molecular heterogeneity). These various profiles also exhibit dynamism  as each cell type responds to the changing extrinsic signals it receives and the intrinsic responses and functions it performs in response. For example, macrophages in the TME may exist in different states that can be M1-like  or M2-like  , 32. HenThe tumor cell compartment of the TME also exhibits spatiotemporal heterogeneity in its genome, epigenome, transcriptome, and proteome profiles. The genetic heterogeneity from acquired mutations is inherent in cancer, with different cancer cells exhibiting some features of their genetic ancestry in a manner that allows investigators to follow the genetic evolution of the cancer cells in a tumor . These vSince it is not possible to cover in depth all forms and mechanisms of heterogeneity, we provide insights mostly from the perspective of responsiveness to therapeutic interventions and the regulation of breast cancer cell fate. For the purposes of this review, we consider cell fate as the balanced outcomes among cell survival-death and proliferation-growth arrest. Readers interested in more in-depth reviews may find the following citations of interest; these address heterogeneity in the context of metastasis –36 and tOne of the clearest examples of cellular heterogeneity is within the TME, which plays a potentially multifaceted role, in collaboration with the extracellular matrix (ECM), in therapy resistance acquisition –46. As nCancer-associated fibroblasts (CAF) are among the most important components of the stromal cell population within the TME, and have been shown to participate in many features of cancer progression including altered drug responsiveness Figure 2CAFs use different/heterogeneous mechanisms to drive ER+ breast cancer cells to acquire endocrine resistance. Mechanisms of the activated TME that can induce therapy resistance include promotion of pro-survival pathways, stemness traits, and/or metabolic reprogramming; CAFs can regulate each of these mechanisms to induce endocrine resistance in ER+ breast cancer cells.pos) and CD146-negative (CD146neg) in luminal breast cancer -expressing CAFs induce tamoxifen resistance involving MEK/ERK signaling in ERα-positive breast cancer cells and tumors . CD63+ Cer cells .Several other studies reported the induction of pro-survival signaling through PI3K/AKT and MEK/ERK by CAFs to promote endocrine resistance –63. For Activated signaling through PI3K/AKT/mTOR is often driven by mutations in either AKT and/or PIK3CA –66 and iExamples of metabolic cooperation between CAFs and tumor cells that can alter endocrine responsiveness include the loss of stromal caveolin-1 (Cav-1), a predictive marker of poor clinical outcome in breast cancer patients treated with tamoxifen . Martine+ GPR77+ CAFs induced chemoresistance via sustained secretion of IL-6 and IL-8 (hi CAF microvesicles (MV) which, in combination with hormone therapy, established stromal cancer stem cell (CSC) niches, specifically those with CD133hi cells  lesions that give rise to recurrent invasive breast cancer share some clonal relationship with the initial DCIS , with certain subpopulation of cells showing a highly malignant gene signature . A minorHigh intercell variability at the transcript level may be responsible for metastasis and resistance to chemotherapy that can be attributed to differences in splicing machinery . In ER+ While the use of single cell RNA sequencing has begun to offer new insights into cellular and molecular heterogeneity, many studies inadequately consider the limitations of current technologies. Few methods are yet able to sample more than ~50% of the entire transcriptome, leaving many RNA species undetected. Leveraging bulk sequencing data on the same samples may increase the ability to see further into the transcriptome. While this limitation is clearly problematic for studies into mechanism, it is less challenging for biomarker and similar studies where the entire transcriptome does not need to be sampled adequately.Metabolic reprogramming is a hallmark of cancers that progress , 132 ande.g., DNA synthesis  or the dynamics of microtubule turnover and their function during mitosis .The ability of a systemic therapy to eradicate a tumor and its metastases is largely dependent on the ability to overcome the heterogeneity of responses in individual cells. Drug response heterogeneity is multifactorial and reflects the combined effects of many of the other forms of heterogeneity discussed above. Cytotoxic drugs generally target cellular features or functions associated with replication, 0/G1 and so insensitive to drugs that target the replication machinery while the cells remain growth arrested. This form of resistance is often referred to as ‘kinetic resistance’. Some cells may remain arrested for a sufficient period that the drug target is released from its inhibition before the cells receive and respond to a mitogenic stimulus. Cells can then enter S-phase with the ability to complete the cell cycle and continue to proliferate.Cancer cell replication in solid tumors is asynchronous, with many cells arrested in G1 may further drive them into G0, effectively taking them out of the cell cycle for prolonged periods. This prolonged growth arrest may allow cells that do not undergo cell death in response to the stress of an endocrine therapy to rewire their signaling and cellular functions to ensure that they survive but remain growth inhibited  or AKT (Capivasertib), likely contributes at least partly to the inability of drugs targeting these mutations to yet show a major improvement in overall survival –162. SinOne of these drug response modifying features is the vascular heterogeneity that is often a significant feature of breast and other solid tumors. Systemically administered drugs must reach the cells that express their molecular targets, and do so in sufficient concentrations to kill the cancer cells. Vascular heterogeneity can lead to different perfusion gradients in tumors, where some regions may receive a cytotoxic level of a drug and others do not - also creating a form of spatial heterogeneity. Vascular heterogeneity may induce a multiple drug resistant-like phenotype since inadequate vascularity may prevent many drugs, independent of their chemical structure or mechanism of action, from reaching some areas of a tumor. Regions that are poorly vascularized may also be hypoxic, with induction of hypoxia stress responses already active in surviving cells in a manner that may also confer resistance to some drugs that reach these hypoxic cells –165.Cellular heterogeneity within the TME likely also contributes to drug response heterogeneity. The presence of multiple interacting cell types can alter the drug responsiveness though their ability to communicate and modify cellular and molecular functions. Among the more common mechanisms are paracrine  as noted above for areas of hypoxia.The combined features of cellular, molecular, vascular and spatial heterogeneity are often further modified by temporal heterogeneity. For example, many omics data are collected as massively parallel snapshots of the cell population samples . Tumor cChanges in the TME, including the dynamic influx and activation/inactivation of key immune effector cells, ensure that interactions between the TME and the tumor cell compartment are constantly changing. Over time, some cells acquire the ability to invade locally and eventually leave the primary tumor to seed metastases, such that the genetic, molecular and cellular features of the tumor also change. Each of these, whether alone and/or in combination, may affect the response of a tumor to a drug and may do so differently over time. In this example, time can be temporal or biological, reflecting the evolution of the tumor and its associated TME. Application of a drug can further change these features over time. For example, breast tumors with many growth arrested cells due to an endocrine intervention may be relatively unresponsive due to kinetic resistance. However, once these cells escape inhibition, perhaps with a wave of proliferating cells driving rapid emergence from dormancy (no longer exhibiting kinetic resistance), the same cells may be more responsive to drugs that require cells to be progressing through the cell cycle to be effective.Pharmacogenetic differences, reflecting the differential expression of isoforms of genes that affect drug metabolism, also can affect drug response heterogeneity. This form of heterogeneity is most evident at the population level, and among individual patients rather than within a tumor and its TME –178. Oth9 cells)  . All of 9 cells) –186.Current spatial omics technologies represent only one series of tools with which to explore the complexity of heterogeneity. Given the rapidity of technological advances in general, it is hoped that the current limitations with these tools will soon be overcome. It will be particularly important to constrain the cost and maximize the availability of these and other new technologies not yet brought to market, to allow the full breadth of the research community to have access and so more effectively advance knowledge.All authors contributed to the writing and editing of this review. All authors contributed to the article and approved the submitted version.


Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neurodevelopmental condition, affecting around 5-7% of school-aged childrenThe study by Yang et al.Do the findings by Yang and colleagues imply that children should be systematically screened via PRS to detect those who will likely develop ADHD and increased STU? The simple answer is no. Technically, PRS are defined by the weighted sum of the risk alleles which are associated with a disorder based on data from available Genome Wide Associations Study (GWAS). Currently, due to small effect sizes, ADHD PRS cannot accurately predict individual outcome. In other terms, most of those with high scores on the currently available ADHD PRS will not develop ADHD because “the signal is too weak”So, where does the value of the study by Yang et al. lie? I believe it is in the understanding of the links between ADHD symptoms and STU at different levels, and in the implications for treatment development. By using a multimodal approach with a cross-sectional as well as longitudinal approach, the authors were able to build and test a comprehensive, coherent model linking ADHD and increased STU, spanning from genes to behaviour via brain measures (estimated white matter integrity). In turn, this points to possible intervention strategies. Indeed, there may be several reasons underlying the link between ADHD and STU. For instance, increased STU might stem from the behavioural impulsivity of individuals with ADHD, or increased STU could contribute ADHD symptoms, in particular inattention. However, the study by Yang et al. suggests that both ADHD and long STU share common genetic underpinning and are characterised by possible dysfunctions in white matter tracts related to visual functions. This may result in impaired executive control of visual functions, with enhanced sensitivity to and distractibility by visual stimuli leading to increased STU.If replicated in other studies, the findings by Yang et al., would provide a compelling rationale to assess interventions aimed at restoring or improving these impaired visual functions. To date, the paradigm “gene dysfunction leading to brain imaging alterations, in turn underpinning behavioural manifestations” has not led to relevant innovations in the care of children with ADHD. For instance, meta-analytic evidenceSC declares honoraria and reimbursement for travel and accommodation expenses for lectures from the following non-profit associations: Association for Child and Adolescent Central Health (ACAMH), Canadian ADHD Alliance Resource (CADDRA), British Association of Pharmacology (BAP), and from Healthcare Convention for educational activity on ADHD.


The brain exists in a state of constant activity in the absence of any external sensory input. The spatiotemporal patterns of this spontaneous brain activity have been studied using various recording and imaging techniques. This has enabled considerable progress to be made in elucidating the cellular and network mechanisms that are involved in the observed spatiotemporal dynamics. This mini-review outlines different spatiotemporal dynamic patterns that have been identified in four commonly used modalities: electrophysiological recordings, optical imaging, functional magnetic resonance imaging, and electroencephalography. Signal sources for each modality, possible sources of the observed dynamics, and future directions are also discussed. The modeling of these constantly changing activity patterns in the brain, or spatiotemporal patterns, has become a major focus in recent years. The relative timing of these fluctuations within a neural population is known to be constantly changing. Instead of having precise synchrony, a range of phase offsets is possible. With flexible phase offsets, these fluctuations in neural activity can be viewed as traveling waves of different shapes including plane, radial, and spiral waves.Relating spatiotemporal dynamics within scales is always simpler than relating across scales of organization.A wide range of characteristic spatiotemporal dynamic patterns has been identified at different scales, from single neurons to systems to whole brains. In this review, we discuss systems-level spatiotemporal patterns  in different modalities. Specifically, we survey the main spatiotemporal patterns that have been detected at the mesoscale using electrode arrays and optical imaging and at the macroscale with functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). For a brief overview and comparison of these modalities see A better understanding of how systems-level dynamic patterns vary across modalities and scales will enhance knowledge of the brain’s functional architecture, giving insight into the origins of intentional behavior and the neural correlates of consciousness, and ultimately allowing for a better understanding of the etiology of pathological brain states and disease.22.1Single electrode recording has been in use for decades, but recent advances to multi-electrode arrays have enabled researchers to characterize the macroscopic dynamic patterns. Electrode arrays can be used as a tool to study spatiotemporal dynamics by measuring changes in local field potentials (LFPs). LFPs have several qualities that make them suitable for studying neural brain dynamics. LFPs represent the aggregate activity of small populations of neurons characterized by their extracellular potentials.2.2,–Electrode arrays have been used to identify recurring traveling waves in spontaneous activity in both cortical slices and surface recordings.In vitro experiments have proven to be beneficial for elucidating the mechanism that drives the observed recurrent propagation. Slow rhythmic activity  or calcium (GECIs). The set of optical imaging tools is cell type-specific, less invasive, and able to relate activity and anatomy and to facilitate long-term recordings of individual cell’s activities over weeks.Their differing sources, in turn, impact characteristics of the measured signal including the resolution and signal strength. The typical spatial resolution for population activity is 50 to These tools can be combined with intrinsic optical signal imaging (IOSI), which makes use of the spectral properties of hemoglobin (Hgb), which has different absorption properties when oxygenated or deoxygenated, to measure changes in brain activity.3.2,,,Optical imaging can measure activity from single neurons to cortex-wide spatiotemporal dynamics. Imaging cortex-wide patterns reveal critical neuronal dynamics that have unique spatiotemporal dynamics for slower and faster frequency bands of activity.,Spontaneous infraslow activity  and task-positive networks (TPNs) .16,19 Th,The neural origins and mechanisms underlying the generation of QPPs is an area of active research, but early work with local field potentials and resting-state fMRI (rs-fMRI) in rodents suggests that QPP activity is correlated to infraslow electrical activity.4.2.2,,,Co-activation patterns, or CAPs, are brief periods, a few seconds long, of spontaneous co-activation or co-deactivation between different brain regions. These CAPs represent recurring instantaneous brain states near the temporal resolution of a single fMRI time point.The CAPs method was initially used in rs-fMRI data to decompose spontaneous rs fluctuations of well-characterized networks into distinct CAPs that happen on a smaller dynamic timescale.In addition to rs analyses, CAPs have also been used in task-based fMRI datasets to investigate functional networks. For example, using CAPs analysis, one study found that the typical DMN connectivity and anti-correlation with the TPN was robust across tasks and during rest.,CAPs provide another innovative option for the dynamic analysis of functional datasets to reveal possible patterns and mechanisms that may be missed by traditional static connectivity analysis. However, as with QPPs, or with other types of more recently described dynamic patterns of functional connectivity, the exact neural basis of CAPs is still not well understood.4.2.3Deep learning and artificial neural networks have recently been used to identify characteristic spatiotemporal trajectories in rs-fMRI data.Sobczak et al.4.3Dynamic fMRI analysis of QPPs, CAPs, and other spatiotemporal trajectories already shows great promise in detecting unique spatiotemporal patterns that are missed by traditional static fMRI analysis. Each of these approaches has led to new insights into spatiotemporal dynamics and has generated a validation of the findings shared between the approaches. For example, QPPs, CAPs, and the variational autoencoder approach to spatiotemporal patterns all validate some aspects of DMN/TPN anti-correlation. A common drawback of all of these spatiotemporal analysis methods is a lack of understanding of the origins of the patterns.As previously mentioned, multimodal approaches in animals and humans provide the most promising route to a better understanding of the neural basis of these patterns and to a translational impact. Pairing fMRI with cell-type-specific imaging techniques such as optical imaging, opto/chemo-genetics, or electrophysiology in animal models will lead to better models of the neural substrates of cortex-wide spatiotemporal patterns and give experimental insight into circular causality across scales.55.1,The primary source of the signal captured by electroencephalography (EEG) recordings is the electrical activity generated by postsynaptic potentials in the apical dendrites of cortical pyramidal neurons.,EEG’s sensitivity to electrical events on the order of postsynaptic potentials means it has significantly higher temporal resolution than fMRI. EEG can capture electrical events ranging from millisecond to hundreds of milliseconds.Individual postsynaptic potential events as measured with EEG are extremely small and do not result in a large signal.5.2,,EEG microstates are spontaneous spatiotemporal patterns of electrical activity occurring on the sub-second timescale and lasting between 80 and 120 ms.,,,Similar to functional networks such as the DMN or TPN, defined in fMRI studies, EEG microstates have also led to the description of canonical brain states. Four canonical classes of microstate maps that are reliable across studies have emerged over time.,As with fMRI, combining multiple modalities in both humans and animals may be the most promising route to an integrated understanding of the origins of spatiotemporal patterns such as microstates detected in EEG. In humans, studies have paired EEG with simultaneous fMRI to compare EEG microstates with BOLD activation maps, giving some insight into the source localization of EEG microstates.6,Spontaneous rs patterns travel along brain networks at multiple scales modulating neural activity. These spatiotemporal patterns transverse the mammalian neocortex through its massively interconnected synaptic network in which a vast majority of excitatory synapses onto cortical excitatory neurons come from other cortical excitatory neurons.in vitro recordings of slow oscillations, it was shown that multiunit activity was the strongest and earliest in layer 5.in vivo work and through optogenetic manipulation of layer 5 cells in vivo.,On a mesoscopic network scale, the thought behind the initiation of cortex-wide activity is split into two theories: initiation from persistently active pacemaker cortical neurons or stochastic initiation by temporal summation of spontaneous synaptic activity.,For a macroscopic network scale, neural recordings such as those obtained from EEG, wide-field optical imaging, or fMRI capture the effects of interaction among billions of neurons across the cortex. Connections across large-scale populations are mediated by cortical white matter fibers, which connect nearby regions or long-range areas.77.1Each of the aforementioned modalities has its own strengths and weaknesses as outlined in ,,,EEG is a valuable multimodal tool for correlating electrophysiological events with dynamic patterns. Recent efforts to better understand the origins of EEG microstates have paired EEG with fMRI, in which source localization of microstates can be inferred by comparing simultaneously measured BOLD activation.–,,,,,Simultaneous multimodal methods to measure complementary features of activity using optical imaging and fMRI have also been described.–One of the main limitations of wide-field optical imaging is that it does not allow for the resolution of single neurons, capillaries, or subcortical nuclei.Multimodal fiber photometry has been successfully paired with fMRI in rats, as in Liang et al.A multimodal fiber-optics approach was used in Schwalm et al.Given that complex brain-wide spatiotemporal patterns are unlikely to be driven by the activity of a single brain’s nuclei, the advantage of targeting multiple subcortical nuclei makes multimodal fiber photometry fMRI studies an excellent multimodal approach to studying brain dynamics.  ion imaging.7.2Ideally, to understand the relationship of neural activity across spatial and temporal scales, recordings should be made simultaneously from all neurons in the brain. To date, no imaging modality is capable of this task. Some, such as fMRI, obtain whole-brain coverage but lack sensitivity to individual neurons; others, such as electrophysiology, can detect activity in a single neuron but have limited spatial coverage. This gap is well-recognized in the field of neuroimaging, and improved methods that more closely approach the ideal case are constantly being developed, in part due to support from the BRAIN initiative. Larger microelectrode arrays, optical reporters that provide greater depth sensitivity, and higher resolution fMRI studies have all had a positive impact on the coverage and/or resolution that can be obtained.Functional ultrasound (fUS) also presents a unique and promising approach to studying large-scale spatiotemporal patterns. Initially developed in rats,7.3Many experimental approaches to understanding functional aspects of different stimuli or tasks rely on averaging large numbers of trials to effectively suppress background activity and highlight only activity that is repeatable across trials. However, there is growing appreciation that the dynamics of ongoing, systems-level activity influence activity in different trials and account for much of the variability that is observed. As an example, infraslow dynamic patterns detected with EEG have been shown to have predictive power for the response to incoming somatosensory input. In a 2008 study by Monto et al.,More recently, Iemi et al.Studies such as these provide further evidence that spontaneous background activity heavily modulates or even masks perception and reaction to external stimuli. Further work is needed across modalities and models to better characterize the interplay between multiscale, ongoing activity and behavioral outcomes such as perception or task performance.7.4Recently, GECIs have been combined with fiber photometry and fMRI in mouse models to explore the contribution of astrocytic activity to the BOLD signal and brain-wide patterns. For example, Gray et al.Going forward, multimodal fMRI approaches are the most promising route to a better understanding of the role of astrocytes in brain-wide spatiotemporal dynamics. In addition to pairing cell-type-specific fiber photometry and optical imaging with fMRI, chemogenetics and optogenetics provide experimental options to drive the activity of astrocytic Ca+2 signals and study their role in brain-wide dynamics.7.5,With coordinated patterns of activity at multiple spatial and temporal scales, the brain has all of the hallmarks of a complex system and shares features with other complex systems . New methods for characterizing these complex systems and their cross-scale interactions are continually being developed, and each new tool provides another view of the functional organization of the brain. For example, some research suggests that the brain as a complex system self organizes into a critical state. In this state interactions between system components lead to scale-invariant events that are beneficial for the system performance by obtaining an optimal balance of stability and flexibility.8Through the use of various recording and imaging techniques, considerable progress has been made in elucidating the cellular and network mechanisms involved in coordinated brain-wide dynamics. This review has outlined four commonly used imaging modalities that have provided unique insights at various scales, allowing for a better understanding of the self-organization of the brain.The emergence of self-organization has two directions: the upward or local to global causation and the downward or global to local causation. This results in the circular causality of spontaneous brain activity. The spatiotemporal patterns of this spontaneous brain activity are hard to tackle, in part, because spontaneous activity acts in the absence of outside influences. The patterns found suggest that the largest amplitude and most regular spontaneous oscillations occur at the seemingly “wrong” time, during sleep or when the brain is otherwise disengaged from the environment.There are still many further avenues for investigation of the mechanisms and functions of these spatiotemporal dynamics. Promising future approaches can provide increasingly informative experimental access to dynamic states at different resolutions, providing a path forward for elucidating the patterns involved in creating dynamical brain states that are important in health and disease.