Hereditary angioedema (HAE) is a genetic disorder characterized by re-occurring swelling episodes called “attacks,” usually in the limbs, face, airways, and intestinal tract. New prophylactic therapies have reduced the frequency of these attacks. This study describes results from a literature review and clinician interviews assessing patient HAE symptom experiences and timing, and then evaluates whether existing patient-reported outcome (PRO) tools adequately reflect this experience.A targeted literature review as well as interviews with key opinion leaders (KOLs), were conducted to capture information about the patient experience and their symptoms. An assessment of various PROs was then conducted to determine how well they each covered HAE symptoms and impacts.Nineteen HAE symptoms were identified. KOLs reported that patients on prophylactic therapy experienced some symptoms indicating an attack was imminent, but then never experienced an attack. The comparison of the different PROs found that the Hereditary Angioedema Patient-Reported Outcome was the instrument that most thoroughly examined the symptoms of patients with HAE.Given the introduction of new prophylactic therapies, further research is needed to determine the effect of being attack-free for longer periods of time on health-related quality of life. Hereditary angioedema (HAE) is a genetic disorder characterized by re-occurring swelling episodes, usually in the limbs, face, airways, and intestinal tract . HAE is Angioedema in the extremities and abdomen is the most common clinical symptom of an HAE attack. These main symptoms relate to large amounts of shifting fluids, and pain related to edema around the face, joints, and extremities , 7. WhilGenerally, treatment has focused on limiting morbidity and preventing mortality—thus improving health-related quality of life (HRQoL) . TypicalIn recent years, several new, long-term, prophylactic HAE therapies have become available in various markets. Haegarda® is an example of a plasma-derived concentrate of C1-esterase inhibitor (human) (C1-INH) for subcutaneous administration twice weekly. Lanadelumab (Takhzyro®) is a plasma kallikrein inhibitor  also used subcutaneously once every two weeks. Dosing every four weeks may be considered in some patients, according to the Food and Drug Administration (FDA) package insert . BerotraHAE symptoms across different timepoints in the HAE patient experience need to be considered and carefully defined. To date, the literature has focused on prodromal symptoms occurring just before swelling, during swelling, and immediately after the swelling subsides. However, there is limited evidence of the patient symptom experience in-between attacks. More detailed descriptions are needed, as symptoms and attacks change as patients receive treatment with the newer, long-term prophylactic therapies. Information is also needed on how these changes affect patients’ lives. In turn, this helps determine whether the most important concepts of the patient experience are being assessed.Recent consensus reports on the burden of disease indicate that HAE may be associated with significant disease burden, which interferes with a patient’s quality of life both during and between attacks . DetermiThe primary aim of this paper is to describe the full range of symptoms reported by patients living with HAE and reflected in the literature. This paper also examines the content coverage of current measurement tools, to see if they are adequately capturing symptoms and impacts reported in the literature and by clinicians.A targeted literature review was conducted to identify the common symptoms associated with HAE outside of the attack phase, and to time the symptoms in relationship to an HAE attack. These symptoms could have occurred just before an attack , immediately after the attack as the swelling subsides, and between attacks. Clinical expert interviews (n = 11) were then conducted to further describe the HAE symptoms discussed by patients with their doctors, the timing and duration of symptoms, and the impressions of clinicians from patient reports about symptom changes following the start of long-term prophylactic treatment. Finally, a comparison of content coverage was conducted for the existing HAE-specific assessment tools, to identify whether they were adequately addressing the patient-reported symptoms and impacts on new prophylactic therapies.A targeted search strategy was developed to initiate the literature review. OVID and Medline databases were searched using the categories listed in Table Articles were included if they focused on describing HAE patient symptoms, and described at least one symptom experienced by patients outside the swelling attack period. Reference lists from full-text articles were also reviewed to identify additional, potentially relevant citations. A data extraction template was developed to aid in the literature review. Information extracted from the literature included patient experiences with symptoms and impacts, as well as information about any assessment tools used in these studies.What are the most common prodromal symptoms that you hear about from your patients who still have HAE attacks?What do your patients usually describe as the impacts on their daily lives because of these symptoms that they have before, after, and between HAE attacks?When you think about the symptoms that your patients have in between their HAE attacks, what are your thoughts about the source of these symptoms?When you think about the symptoms that your patients have in between their HAE attacks, what are your thoughts in general about treating and managing these between-attack symptoms?US-based clinical experts were identified from those frequently presenting at HAE meetings, as well as published specialists who are active in HAE research and treatment. Nineteen clinicians were identified from academic centers, large referral centers, and private practice; eleven agreed to participate in the qualitative interviews. Reasons for non-participation included lack of time to be involved, prohibitive contracting issues, and conflict of interest. A semi-structured qualitative interview guide was developed to facilitate discussion with clinical experts regarding HAE symptoms described by patients. Clinician interviews were conducted by trained qualitative interviewers and lasted approximately 60 min. Sample interview guide questions included the following:Interviews were audio-recorded and transcribed; transcripts were used for qualitative analysis. Areas of key interest included patients’ descriptions of their symptoms, when those symptoms occurred relative to the swelling attack, and the types of changes reported following the start of long-term prophylactic treatment.The resulting symptom and impact concepts identified in both the literature and clinician interviews were used to develop a conceptual disease model (CDM) that describes the patient experience with symptoms, impacts, severity, and treatment. The most frequently cited symptoms and impacts from the literature review were used to develop the CDM. This was later updated using the clinician interview results.While previous work went into the development of HAE-specific disease models , our CDMSeveral HAE-specific HRQoL assessment tools (PROs) were identified during the literature review. These PROs were reviewed for specific content coverage across the spectrum of patient-reported symptoms and impacts. The PROs that were identified as HAE-specific included the following: the 17-item Angioedema Quality of Life Score (AE-QoL) , the 25-Of the 131 records identified in the literature review, 29 were removed after limits were applied. Articles removed at this point included those published in a language other than English, outside the 2009 to 2019 timeframe, and on non-human subjects. Twenty duplicate entries were also removed, leaving 82 records to be screened using the eligibility criteria. Sixty records did not meet the eligibility criteria, which yielded seven full-text articles and 15 conference abstracts for review and data extraction. The studies covered in the published literature presented information from the patient perspective, with one exception—presenting information based on the clinician’s view of the patient perspective  were fatigue, erythema marginatum, paresthesia, stinging, tingling, abdominal issues , nausea, vomiting, pain, rash, flu-like symptoms, pruritus, and rumbling throughout different body parts. Additional symptoms reported included irritability/short temper, bruises, transitory edema, appetite changes, headache, fatigue, restlessness, excessive perspiration, changes in body temperature, and psychological issues (including depression/sadness and anxiety).Although patient symptoms were identified throughout the literature, the timing of symptoms occurrence was most often described as “prodromal”  or during the swelling episode. Symptoms were seldom reported as occurring while the swelling subsided or in between attacks.Eleven interviews were conducted with the identified clinical experts. Four clinicians were from academic centers, two were from large referral treatment centers, and five were in private practice. The private practice settings treated 25–100 HAE patients, and the case load at the larger academic centers ranged from 100 to 180. The majority (75–95%) of the patient groups treated by interviewed clinicians were type I or type II HAE.Although there was broad acknowledgement that symptoms occurred outside of the swelling episodes, there was no consensus on how to precisely define the attack period—as well as the post-attack period—versus those symptoms occurring between attacks. In describing prodromal symptoms, most clinicians (n = 8) described this as any symptom experienced within a couple hours to a couple of days before the swelling episode (or the attack), whereas a few characterized these symptoms as specifically attack-related. Most clinicians (n = 8) described patients experiencing symptoms occurring just prior to the swelling, during the actual swelling episode, after an episode as the swelling subsides, or in between episodes—which excludes the other time periods described above. This reflects how HAE symptoms could occur on a continuum.While clinicians reported many of the same symptoms appearing in the literature, their interviews added more detail about these symptoms. For example, the physicians focused on different types of swelling based on the anatomical locations involved, and the timing of the symptoms in relation to swelling episodes. Clinician-reported symptoms included general swelling, facial swelling, throat swelling, and peripheral angioedema in the hands or feet. Other non-swelling symptoms mentioned during clinician interviews included fever, general aches and pain or muscle aches, numbness, the sensation of feeling “run down” or having fatigue, and non-swelling abdominal symptoms . Except for the primary swelling symptoms that characterize HAE attacks, the symptoms that patients reported to clinicians occurred both before their HAE swelling attacks, and again after the swelling attack had peaked. In some cases, fatigue and abdominal symptoms continued into the period between HAE attacks. Other symptoms like rash, flu-like symptoms , and various paresthesias  were experienced just prior to and following the acute attacks (as the swelling subsides). Of note, these were not reported in between attacks.Finally, emotional symptoms  were reported throughout the HAE patient experience. Anxiety would focus on when another attack would begin. Once the attack started, the anxiety would switch to how severe the swelling would be before subsiding. Sadness and depression were experienced throughout the different HAE phases, related to the quality-of-life disruption.One of the most prominent changes clinicians heard from patients being treated prophylactically with C1 INH inhibitors (such as Haegarda® and Firazyr®) or monoclonal antibodies (like Takhzyro®) was that they still experienced symptoms associated with attack onset—but now that they were on prophylactic treatment, these symptoms were not followed by an attack.As noted earlier, some of the symptoms reported in the literature were not always categorized by the timing in relation to swelling episodes. Thus, this information was not available for all symptoms. Also, clinicians’ responses regarding when their patients’ experienced symptoms were based on anecdotal recall of conversations with patients; it should be noted that this is not a typical line of inquiry in the clinical setting. Therefore, timing for only 19 symptoms was reported in the literature and clinician interviews Fig. . FourteeOf the 19 symptoms identified in the literature review and clinician interviews with a timing designation, rash and fatigue were most often identified before and after an attack. Clinicians described swelling in the hands, fingers, feet, face, and abdomen as the most common prodromal symptoms—as well as key attack symptoms. Rash and fatigue were also commonly cited in the literature as prodromal.The CDM describes how various environmental, behavioral, and health conditions—in combination with patient attributes—influence HAE severity, swelling severity and frequency, and the pattern and duration of signs and symptoms. HAE severity influences treatment choice—particularly for long-term prophylaxis, which in turn influences the patient’s symptom experience, emotional impacts, and activity limitations Fig. .Several assessment tools were mentioned across both the literature review and clinical expert interviews. Those considered for content comparison include the five-item AAS , 24, theThe content of these tools was mapped to compare differences between measures. The PROs identified varied in length. Some were four-item measures, while others included up to 27 items. The recall periods also varied, ranging from “None defined” (HAEA-QoL and HAE-PRO) to “past 6 months” (HAE-QoL and HAE-AS). This is important to note because clinicians described widely varying timeframes for both symptom occurrence and intervals between attacks. No instruments inquired about the time period where symptoms occurred—effectively preventing the assessment of changes in symptom and attack timing that many patients starting prophylaxis experience. Table The AE-QoL is largely a quality of life measure more focused on impacts— not symptom coverage. Emotions such as anxiety or depression are coded with impacts, since they are a disease impact rather than a direct HAE symptom. The HAE-PRO and HAE-AS have detailed coverage of the swelling symptoms associated with attacks, but the HAE-PRO is the only instrument that provides any substantial coverage of other non-swelling symptoms. Only the HAE-PRO and HAEA-QoL address fatigue, which was frequently reported in both the literature review and clinician interviews. Only the HAE-PRO assesses attack severity and symptoms duration, and only the AAS addresses the overall severity of swelling and pain .Interference with work, productivity, and daily activities are covered in varying detail by several instruments. The primary categories of life interference and burden identified in the literature—and mentioned in the clinician interviews—were the impact on work and productivity, social relationships, emotions, and the ability to resume greater normalcy in daily life activities. The HRQoL and impact coverage of each assessment tool are further described in Table While some measures focus more on assessing the patient’s symptomatic experience, others more broadly assess HAE disease burden—specifically, how much HAE might impact an individual’s daily functioning or overall quality of life. In this sense, disease burden reflects the degree to which symptoms might interfere with daily activities or overall quality of life. Although the AE-QoL, HAEA-QoL, and HAE-QoL do not cover symptoms, these two measures do have better coverage for emotional impacts. Similarly, the four-item AECT also evaluates HRQoL, specifically by assessing symptom bother and how well the prescribed therapy controls HAE. In looking across Tables When describing patient-reported symptom changes, clinicians described significant changes in severity and duration with both C1 INH inhibitors and monoclonal antibodies. Only the HAE-PRO asks participants to describe symptom severity and duration. However, the AECT describes how bothersome these symptoms were and how well they are controlled by treatment.. The symptoms that are covered in existing HRQoL instruments have been highlighted in blue. The symptoms reported in the literature and discussed by clinicians but not covered in existing HAE instruments have been highlighted in green.In addition to comparing each PRO’s content to each other, we also compared the symptoms and impacts identified in the literature and clinical expert interviews Table . The 29 Based on this comparison, only the HAE-PRO, AAS, HAE-AS, and HAEA-QoL adequately assessed the symptoms described in the literature review and by clinicians. Of these four instruments, only the 18-item HAE-PRO identified more than three symptom categories. The HAE-PRO and HAE-AS provide the best detailed coverage of swelling symptoms by location, and the HAE-PRO provides the best coverage of non-swelling symptoms. Skin redness, rash, and eruptions are only covered by the HAE-PRO. Fatigue (including feeling tired and run down) is only covered by the HAE-PRO and the HAEA-QoL Table .Symptoms identified from the literature review and expert clinician interviews—but not assessed in the assessment tools themselves—included flu-like symptoms, fever, itching, and nausea. Additionally, paranesthesia, numbness, and tingling were also reported in both the literature and by clinicians, and discussed as important prodromal symptoms—yet not reflected in any instruments. Finally, less commonly reported symptoms  are also not covered in the instruments Table .The most frequently reported symptoms in both the literature review and clinical interviews included fatigue, rash, and abdominal symptoms. During an attack, the most frequently reported symptoms in both the literature and clinician interviews focused on different swelling symptoms. While swelling symptoms were reported before or during an attack, non-swelling symptoms were also reported before and after attacks, as well as in between attacks. Although no specific consensus was reached about the definitions of “before, during, after, and between” attacks, it was generally recognized that symptoms occur outside the swelling episodes. The information gained from the literature and clinician interviews shows a much broader patient experience with HAE symptoms and impacts. Additionally, all clinicians recognized that the current focus of patient care has moved from attack-specific to a broader, more holistic definition of disease burden. Clinicians also felt that they have been hearing this broader picture of symptom-related impacts from their patients.The current PRO tools may not fully reflect the symptom experience of HAE patients across this continuum of symptoms in their everyday lives. While the identified instruments have different recall periods, none of them assess the timeframe in which a particular symptom occurred, whether that be before, during, after, or in between an attack. More research may be needed to better define and distinctively outline these timeframes. Additional research is needed to better understand and describe the changes occurring in symptom frequency and severity, attack frequency and severity, and duration for patients living with HAE and starting new prophylactic therapies. Qualitative interviews with patients who live with HAE and have experienced different treatment regimens will be required to better understand the impact of long-term prophylactic therapy and confirm whether being attack-free for longer durations effects on patients’ emotional well-being and functional status across all time periods. Further, it is unclear whether the patient-reported HAE symptoms in this study were side effects of the prophylactic treatments being taken. Larger quantitative studies are also needed to differentiate between symptoms and treatment side effects at different timepoints.Clinicians described their HAE patients as having difficulties with anxiety and depression, both before and after acute attacks. This suggests that patients living with HAE experience both physical symptoms and emotional impacts. Further research is needed to characterize patients’ emotional impacts, and if they change following the start of long-term prophylaxis. It is noteworthy that patients with long-term prophylactic therapy still experience prodromal symptoms that do not necessarily lead to an intensification of the swelling episode, because their anxiety level about an impending attack will likely lessen .Several PRO instruments exist, and collectively they address many of the HAE symptoms faced by patients. However, of the seven PROs assessed, only the HAE-PRO adequately addressed the symptoms raised in the literature review and clinical expert interviews; however, several key areas remain unaddressed. Only the HAE-PRO assessed the attack severity and symptom duration, and only the AAS addresses the overall severity of swelling and pain—but in general, rather than for specific symptom locations. The AECT also asks participants to describe how bothersome these symptoms were and how well they were controlled by treatment. The AE-QoL and HAEA-QoL provided the most content coverage for the impacts raised by patients living with HAE, both in the literature and from clinical expert interviews. In looking at an evolving patient experience, it is important to re-evaluate what concepts are being assessed, the length of time these concepts occur, whether these are the best concepts to reflect the treatment goals, and whether they are being covered by existing HAE-specific PRO assessment tools.Although the current research is based on a small sample of expert clinicians and a targeted literature review, the results show that HAE symptoms are not limited to only those experienced during HAE swelling attacks. Many different symptoms  may also occur at different times. As the symptom experience varies widely across patients, clinicians have heard patients describe changes in their symptom severity and noticed a pattern of symptom occurrence from the new prophylactic treatments.From the review conducted, very few HAE assessment tools reflect the changing patient experience and include the symptom experience in all time periods (apart from the swelling episodes). Patients experience a wide variety of HAE symptoms, thus making an assessment of all of symptoms infeasible. However, some frequently experienced symptoms, and those often preceding attacks , should be considered as part of a thorough assessment of patient HAE status utilizing HAE PROs. Yet no existing HAE instruments reflect these concepts.Other aspects of the symptom experience may be more important to capture, such as specific symptom severity and duration, and overall attack severity and duration—especially since these are aspects where patients and clinicians report change due to the new prophylactic treatments. These are areas that may be more meaningful to patients, and possibly more reflective of treatment benefit. With the advent of new HAE prophylactic therapies, patients experience fewer HAE attacks, and the intervals between HAE attacks may increase . These t


CaSR) in FHH 1 or its downstream regulatory pathway in FHH2 and FHH3. In children, adolescents and young adults with FHH the main challenge is to distinguish the condition from primary hyperparathyroidism and thereby to avoid unnecessary treatments including parathyroidectomy. However, inheritance of FHH may result in neonatal hyperparathyroidism (NHPT) or neonatal severe hyperparathyroidism (NSHPT), conditions with high morbidity, and in the latter even high mortality. This review focuses on the genetic and pathophysiological framework that leads to the severe neonatal form, gives recommendations for counselling and summarizes treatment options.Familial hypocalciuric hypercalcemia (FHH) is a mostly benign condition of elevated calcium and PTH levels based on a hyposensitive calcium sensing receptor ( Loss-of-function (LOF) mutations in the calcium-sensing pathway may cause various calcium-hyposensitivity-diseases which are characterized by elevated serum calcium levels. Pathophysiologically, this is based on a shift of the ‘set point’ of the calcium concentration at which PTH secretion is half-maximal . The resCaSR) and accounts for about 65% of all FHH cases ..CaSR froCaSR due to hypercalcemia , which is involved in clathrin-mediated CaSR endocytosis. The mutant AP2σ leads to enhanced CaSR cell-membrane expression but also impaired CaSR signaling  is a clinically severe, ultra-rare disease associated with a high mortality usually caused by homozygous or compound heterozygous inactivating mutations in CaSR [In contrast to the clinically benign course of FHH, neonates with de-novo or paternally derived mutations in PT OMIM #39200 is  in CaSR . Infants in CaSR ,42,43. SCaSR [Milder phenotypes are termed neonatal hyperparathyroidism (NHPT). These conditions are characterized by elevated serum PTH levels and subsequent bone disease, however only moderate hypercalcemia. Infants with NHPT are typically symptomatic as hypercalcemia leads to poor feeding with resulting dehydration, and lethargy, while PTH excess causes skeletal demineralization. These patients usually carry heterozygous, LOF- mutations in CaSR .CaSR mutations is not only defined by the underlying genetic mutation but is significantly modified by the parental origin of the mutation , a condition that is ultra-rare in pediatric patients and has never been reported in neonates . As suchfindings .In the clinical practice for older children (often adolescents) and adults, the differential diagnosis between primary hyperparathyroidism (PHPT) and FHH is essential, as parathyroidectomy may be indicated in PHPT and in neonates with NSHPT but usually not in older patients with FHH ,52,53.Recommendations on the practical management of parathyroid disorders is provided in the recently published European expert consensus paper .In cases of chronic hypercalcemia, it is of utmost importance to measure calcium excretion in the urine. Neither the calcium level nor the PTH level allows a differentiation of FHH and PHPT . HoweverIn 2018, Bertocchio et al. introduced the pro-FHH (probability of having FHH) score with a specificity for FHH and PHPT of 100%. Pro-FHH takes plasma calcium, PTH, and serum osteocalcin concentrations, and CCCR calculated from 24-h urine collection into account . HoweverCaSR gene analysis. The clinical presentation in FHH1 and FHH2 is usually similar. Mutation analysis of AP2S1 gene for FHH3 should be performed in FHH patients with marked hypermagnesemia, cognitive impairment and low bone mineral density [Vargas-Poussou et al. compared a large cohort of FHH and PHPT patients and found considerable overlap in the phenotypes, making the distinction based on laboratory data alone difficult . Thus, C density .A specific treatment is not necessary in the majority of patients. In contrast, morbidity may result from inappropriate surgical intervention . The proHowever, in rare instances when calcium levels are very high or the patients become symptomatic from hypercalcemia, it becomes necessary to treat FHH ,61.CaSR [CaSR in the parathyroid cell, thereby decreasing PTH secretion and consequently serum calcium levels. In FHH, cinacalcet results in a significant reduction of serum calcium levels and improvement of calcium clearance after initiation of cinacalcet therapy [Calcimimetic drugs, such as cinacalcet, are allosteric agonists at the CaSR . They en therapy ,65,66,67Treatment with cinacalcet has also been reported in FHH2  and FHH3Based on the fact that most patients with FHH do not require any form of treatment and that patients are at risk of unnecessary  parathyroidectomies the focus is based on (genetic) counselling . PerinatTherefore, we agree with the recommendation of Ghaznavi et al., that it is advisable to offer genetic counseling to all pregnant women with confirmed FHH or a partner with FHH given the range of possible neonatal outcomes , includiCaSR are at risk to develop NHPT or even NSHPT. This risk is highest if the mother is not affected by FHH or if homozygous or compound heterozygous mutations affect the neonate. In NHPT clinical signs are often temporary and resolve within weeks or months once the neonate has established calcium levels according to her/his individual threshold. At that point, the excess PTH will drop to the individual threshold and the skeletal system may mineralize appropriately in the further course. However, in NSHPT (due to homozygous or compound heterozygous mutations in CaSR), therapeutic interventions must aim to lower calcium and PTH levels until a diagnosis is established and a definite  treatment can be pursued. Adult patients with FHH of reproductive age should be counselled about the potential peripartal complications in this condition.While FHH in general is a benign condition, neonates with inactivating mutations in


Monitoring shifts in vegetation composition over time is essential for tracking biodiversity changes and for designing ecosystem management strategies. In Australia, the Terrestrial Ecosystem Research Network (TERN) provides a continent-wide network of monitoring sites (AusPlots) that can be used to assess the shifts in vegetation composition and structure of Australian Major Vegetation Groups (MVGs). Here we use time-series site data to quantify the extent and rate of MVG shifts between repeat visits and to recommend the most appropriate sampling frequency for specific MVGs. The research area spans a ~1,500 km latitudinal gradient within south/central Australia from arid rangelands in the north to Mediterranean vegetation in the south. The standardized AusPlots protocol was employed to repeatedly survey 103 one-hectare plots, assessed between 2011 and 2019. Floristic and growth form dissimilarities between visits were calculated with distance metrics and then regressed against survey interval. Multivariate ordination was used to explore temporal floristic shifts. Rank-dominance curves were used to display variations in species’ importance. Between repeated visits, sites exhibited high variability for all vegetation parameters and trajectories. However, several trends emerged: (a) Species composition moved away from baseline linearly with intervals between surveys. (b) The rate of species turnover was approximately double in communities that are herbaceous versus woody-dominated. (c) Species abundances and growth forms shift at different speeds. All floristic and structural metrics shifted between re-visits, with varying magnitude and speed, but herbaceous-dominated plots showed higher floristic dynamism. Although the expanse, logistics, and the short time between visits constrained our analysis and interpretation, our results suggest that shorter revisit intervals may be appropriate for herbaceous compared to woody systems to track change most efficiently. In Australia, rangelands are defined as land supporting low-intensity and extensive livestock grazing. They extend over 81% of the continent, from the northern monsoonal savannas to the southern temperate lands that bound the central deserts . Rangelahttps://www.tern.org.au) and it is opportune to assess the changes that this monitoring program can capture. Whilst the TERN program has continental coverage, we focus our analysis here on vegetation shifts of arid rangelands of central Australia and their gradual transition to southern Mediterranean-type woodlands. Both landscapes are characterized by old, geologically diverse substrates, with mostly infertile soils with highly variable rainfall. This combination of abiotic conditions, modulated by fire and human intervention, underpins the vastly heterogeneous and fragile vegetation types  and ed plots  and our Cenchrus ciliaris) in some areas have diminished vegetation diversity by outcompeting native species and by increased frequency and intensity of fire  and relative frequency [ *100] were calculated. Adding relative species cover and frequency generates the species IVI. Similarly, the IVI of each growth form was assessed by adding their relative number of species and its relative number of PIs. Species richness and Shannon and Simpson indices assess species diversity and relative dominance. The Sörensen (Bray-Curtis) distance and the Simpson Beta metrics , represe(DOCX)Click here for additional data file.


In neuroscience, electroencephalography and neuroimaging techniques are widely used to improve our understanding of brain mechanisms and to identify biomarkers for the most diverse neurological pathologies .Yang et al.). In particular, EEG and fNIRS were selected as noninvasive neuroimaging modalities in this systematic review. Nine brain disorders were investigated in this review, including Alzheimer's disease, depression, autism spectrum disorder, attention-deficit hyperactivity disorder, epilepsy, Parkinson's disease, stroke, schizophrenia, and traumatic brain injury. This review showed that most of the articles (82.6%) employed transcranial direct current stimulation (tDCS) as an intervention method with modulation parameters of 1 mA intensity (47.2%) for 16–20 min (69.0%) duration of stimulation in a single session (36.8%). The author concluded that future work needs to investigate a closed-loop tES with monitoring by neuroimaging techniques to achieve personalized therapy for brain disorders.One of the reviews focuses on investigating brain disorders using tES in combination with non-invasive neuroimaging techniques. The review highlights shortcomings and provides a comprehensive guideline for further investigation (Scrivener). Overall, this article aims to equip new researchers with the resources needed to make an informed decision regarding the necessity of simultaneous EEG-fMRI. As multi-modal neuroimaging requires additional time, equipment, and financial resources, it is essential to consider the recording options available thoroughly. Furthermore, ongoing technological and methodological developments continue to facilitate the successful application of combined EEG-fMRI to answer questions about the brain and behavior with increasing precision.The second review includes a flow chart of questions that researchers can consider when deciding whether to record EEG and fMRI separately or simultaneously  showed robust relationships between EEG and EMG signals that might be of some interest for analyzing neuromotor disorders, such as Parkinson's disease, to identify neural correlates of abnormal gait. In another study, the authors  have developed a new measure named normalized compression distance (NCD) to measure cortico-muscular synchronization using EEG and EMG data. A third study employed a coupled tensor decomposition to extract the signal sources from MEG-EEG during intermittent photic stimulation (IPS). There, Coupled Semi-Algebraic framework for approximate CP decomposition via SImultaneous matrix diagonalisation (C-SECSI) was able to separate physiologically meaningful oscillations of visually evoked brain activity from background signals. The component frequencies are able to identify either an entrainment to the respective visual stimulation frequency, its first harmonic, or an oscillation in the individual alpha band or theta band. A reciprocal relationship between alpha and theta band oscillations is present in the group analysis of both EEG and MEG data. The coupled tensor decomposition using the C-SECSI framework is a robust, powerful method for the unsupervised extraction and separation of meaningful sources from multidimensional biomedical measurement data . Finally, another study combined EEG and MEG data using microstates modeled from subject- and modality-specific archetypes that represent distinct topographic maps between which the brain continuously traverses. The implemented method successfully models scale and polarity invariant data, such as microstates, accounting for intersubject and intermodal variability. Furthermore, the model is readily extendable to other modalities ensuring component correspondence while elucidating spatiotemporal signal variability .In addition to the reviews, eight original studies analyze the combination of electrophysiological techniques. While some studies focused on combining EEG and Electromyography (EMG) others combined electro- and magnetoencephalography (E-MEG). One of the studies combining EEG and EMG  in Li et al., whereas a modeling framework based on fNIRS as a complementary approach to EEG is proposed for the discrimination of single trial task responses for brain computer interfaces (BCI) in Zhang et al..The utility of electroencephalography for diagnostics is further highlighted both considering Alzheimer's disease (AD) and Stroke. For AD, topological features of networks constructed for each EEG channel based on weighted visibility graphs were considered in Overall, this Research Topic shows the fronts in combining EEG with other techniques to study dynamic brain functions or changes from a temporal and spatial perspective. These include technical possible study design, data acquisition, and data analysis to improve human health by combining advanced brain technologies with cutting-edge science and original bio-medical insight. This challenge requires creative problem-solving, precision and a lot of imagination. There is a big challenge in removing artifacts to perform fully continuous EEG-fMRI/TMS/tDCS/tES recordings. This will be the mainstay of multimodal functional brain imaging. Neuroimaging-techniques is an area that needs further research and validation of algorithms.Finally, clinical applications have thus far been limited. In the future, combined neuroimaging studies will help neuroscientists to extract neuro-information underlying sensory and cognitive activity in healthy and pathological conditions.All authors contributed to the article and approved the submitted version.


Osteosynthesis systems are used to fixate bone segments in maxillofacial surgery. Titanium osteosynthesis systems are currently the gold standard. However, the disadvantages result in symptomatic removal in up to 40% of cases. Biodegradable osteosynthesis systems, composed of degradable polymers, could reduce the need for removal of osteosynthesis systems while avoiding the aforementioned disadvantages of titanium osteosyntheses. However, disadvantages of biodegradable systems include decreased mechanical properties and possible foreign body reactions. In this review, the literature that focused on the in vitro and in vivo performances of biodegradable and titanium osteosyntheses is discussed. The focus was on factors underlying the favorable clinical outcome of osteosyntheses, including the degradation characteristics of biodegradable osteosyntheses and the host response they elicit. Furthermore, recommendations for clinical usage and future research are given. Based on the available  evidence, biodegradable copolymeric osteosyntheses are a viable alternative to titanium osteosyntheses when applied to treat maxillofacial trauma, with similar efficacy and significantly lower symptomatic osteosynthesis removal. For orthognathic surgery, biodegradable copolymeric osteosyntheses are a valid alternative to titanium osteosyntheses, but a longer operation time is needed. An osteosynthesis system composed of an amorphous copolymer, preferably using ultrasound welding with well-contoured shapes and sufficient mechanical properties, has the greatest potential as a biocompatible biodegradable copolymeric osteosynthesis system. Future research should focus on surface modifications  and novel biodegradable materials  to address the disadvantages of current osteosynthesis systems. Most of the osteosynthesis systems applied in oral and maxillofacial surgery (OMF-surgery) consist of plates and screws. In maxillofacial traumatology, osteosynthesis systems are used for fixation of bone segments after anatomical reduction of dislocated or mobile fractures. In orthognathic surgery, they are used for fixation of osteotomy segments in a predetermined position to treat maxillofacial deformities.Titanium osteosynthesis systems are currently the gold standard for maxillofacial fracture treatment and orthognathic surgery. The titanium plate and screw combination has excellent mechanical and handling properties, providing adequate bone stability with clinically acceptable plate and screw dimensions without the need for rigid maxillomandibular fixation ,4,5,6,7.The potential of using biodegradable biomaterials to increase health-care quality and reduce costs has led to a substantial increase in interest in biomaterials by researchers as well as clinicians over recent years ,17,18. COver the last few decades, both the titanium and biodegradable osteosynthesis systems have been improved ,22. ExamThis review explores advances gathered from in vitro and in vivo studies  on biodegradable and titanium osteosyntheses in maxillofacial surgery. First, the osteosynthesis concepts in maxillofacial surgery are briefly summarized. Next, the factors underlying the favorable clinical outcome of biodegradable osteosyntheses as an alternative to titanium osteosyntheses based on pre-clinical evidence are reviewed, including the physico-chemical and mechanical properties of the (co)polymers as well as the degradation characteristics and the host response they elicit. Then, the clinical outcomes of both types of osteosyntheses are compared and discussed based on the available evidence followed by clinical recommendations. Finally, leads for future research are given and future directions for the clinical translation of novel biomaterials are discussed. Together, these aspects will guide evidence-based selection of osteosynthesis systems in maxillofacial surgery and target future research.A biodegradable osteosynthesis system should meet two intertwined criteria to be used as an osteosynthesis system: (1) the biomaterial needs to be biocompatible with the host tissue and (2) the mechanical properties should be sufficient for stable fixation of fracture or osteotomy segments during the surgical procedure (primary stability) and during the degradation of the biomaterial, with a gradual transfer of stress to the healing bone .Implanted materials evoke an initial host response after implantation that includes inflammation, proliferation and tissue remodeling, and, in the case of biodegradable biomaterials, is affected by the degradation products . This ho+ T-cells of the adaptive immune system. T helper 1 (TH1) cells can induce M1 macrophages by producing interferon-γ and IL-2 ..co-glycoSynthetic polymers undergo biodegradation via two different modes depending on the rates of bond cleavages and water diffusion into the polymer: bulk and surface degradation. In bulk degradation, the degradation occurs in the complete implant resulting in a decrease in molecular weight and molecular strength with time. Since the complete implant degrades at a similar rate, disintegration of the implant with generation of polymeric debris can occur. In contrast, surface degradation occurs on the surface of the implant, resulting in a decrease in size and mass of the implant with time. Here, the molecular weight and mechanical properties of the material remain relatively unchanged .Extracellular degradation of poly(α-esters) occurs through hydrolysis (two phases), enzymatic degradation, and oxidation. During hydrolysis, cleavage of the ester bonds by water results in oligomers and monomers, such as lactic acid and glycolic acid (primary hydrolysis) ,45, thatBiodegradable osteosynthesis systems should, preferably, be completely resorbed within 12 months . HoweverThe progression of the host response is affected by the acidic degradation products of the poly(α-esters). A lowering in pH intensifies the inflammatory response that results in fibrous encapsulation of the implant ,51. FurtCurrently, two main hypotheses regarding the etiology of foreign body reactions to these synthetic polymeric biomaterials exist. After implantation, the biodegradable polymers are encapsulated by fibrous tissue that acts as a semi-permeable membrane . The firDifferences in vascularization also contribute to inducing foreign body reactions. Sufficient vascularization is necessary for adequate bone healing, but it is also essential to eliminate the acidic degradation products of the hydrolyzed poly-α-esters , thereby affecting the equilibrium between the levels of degradation products and the ability of the host to eliminate the degradation products . Accumulco-30DLLA)], Inion CPS [poly([70–78.5]LLA-co-[16–24]DLLA-co-4TMC)], SonicWeld Rx [poly(DLLA)], and LactoSorb [poly(82LLA-co-18GA)] biodegradable osteosynthesis systems. The copolymer of the SonicWeld Rx system was the only one that was amorphous; all the other assessed systems were semi-crystalline. All the biodegradable systems were safe to use and well-tolerated. The SonicWeld Rx system showed the most predictable degradation profile. In addition, together with the LactoSorb system, new bone percentages similar to negative controls were observed after 18 months while the two other included systems reached these levels after 36 months  biocompatibility and degradation of four commonly used biodegradable copolymeric osteosynthesis systems was compared using a goat model . The stu6 months . However6 months , were ob6 months .Since the crystalline regions of synthetic (co)polymers, the intermediate degradation products and the crystalline oligomeric stereo-complexes that can be formed in vivo over time are hydrophobic ,58,62, tOther than (co)polymer composition, the geometry and surface topography of the implanted materials also affect biocompatibility in vivo . Thick bBiodegradable metals are promising alternatives to polymeric osteosynthesis systems due to their mechanical properties that are closer to bone than (co)polymeric materials  and thei2, Fe(OH)3, and Fe3O4, that inhibits further degradation. As a result, the degradation rate of Fe-based metals is very slow . S. S105]. Staphylococcus aureus, the most common etiological pathogen of infections surrounding osteosyntheses . I. I110]. yntheses ) is negayntheses . By modiSeveral studies assessed the mechanical forces surrounding osteosyntheses applied to maxillofacial fractures ,162,163,The mechanical properties of osteosynthesis systems depend on several factors including composition  or (co-)polymers), the production processes  ,118,174,In a recent in vitro study, the maximum tensile load as well as the tensile, bending and torsional stiffness of 13 biodegradable and 6 titanium straight, four-hole osteosynthesis systems derived from static mechanical tests of the initial materials were assessed and compared  20]. Th. Th20]. Within the limitations of finite element analyses , three-dimensional analyses indicated that the biomechanical stresses surrounding osteosynthesis systems remain far below the threshold of their ultimate strength of both biodegradable and titanium osteosynthesis systems ,182,183.Finite element analyses also demonstrated that the stress surrounding conventional screws is much larger compared to those of plates, indicating that material complications may arise from the screws rather than the plates  . The posIn theory, the primary advantage of biodegradable compared to titanium osteosynthesis is the reduced, or even eliminated, need for symptomatic device removal while having similar efficacy . In a recent systematic review with meta-analyses, the available clinical evidence  from patients treated for maxillofacial fractures  with load-sharing biodegradable versus titanium osteosyntheses was compared . FollowiSimilar to the abovementioned results, a recent systematic review with meta-analyses that compared biodegradable versus titanium osteosyntheses in adults with dentofacial deformities treated with orthognathic surgery , and intraoral vertical ramus osteotomies (IVRO), with and without concurrent genioplasty) also demonstrated similar efficacy and morbidity between biodegradable and titanium osteosynthesis systems . Non-comIn contrast to the abovementioned trauma population , a non-sAn important aspect of successful biodegradable osteosyntheses  is the biomechanical perspective. The biomechanical differences between fixation of fractures and osteotomies may explain the beneficial effect of biodegradable systems compared to titanium systems after fracture fixation versus osteotomy fixation. Fracture fixation with interfragmentary stability ensures load-sharing osteosyntheses whereas in osteotomies, interfragmentary stability is absent and thus the complete load at the osteotomy is carried by the osteosynthesis system  ,203. SinThe clinical evidence of biodegradable metals is limited. A clinical study that compared magnesium  with titanium compression screws  for the fixation of mandibular condylar head fractures showed similar results after 18-month follow-up, with limited formation of hydrogen gas within the first 4 months . These aAt first glance, the non-significant difference in the proportion of symptomatic removal of biodegradable and titanium osteosyntheses in orthognathic surgery seems to negate the benefits of biodegradable osteosyntheses. However, asymptomatic biodegradable osteosynthesis systems will eventually be resorbed while titanium osteosynthesis will remain in situ until removed surgically. Therefore, titanium osteosynthesis systems have a life-time risk of, e.g., late infection or palpability complaints. Furthermore, biodegradable osteosyntheses have other (secondary) advantages, besides the most obvious benefit of less device removal compared to titanium systems, including no interference with radiographic imaging and radiotherapy, a more gradual transfer of stress to the healing bone , and less system palpability in the long-term ,214,215.Similarly, after fracture fixation in pediatric patients, common practice is to electively remove all the titanium systems due to possible later growth disturbances ,222 and An important aspect when assessing efficacy, morbidity and symptomatic osteosynthesis removal in clinical studies is the duration of follow-up. The studies included in the most recent and comprehensive systematic reviews that focused on biodegradable versus titanium osteosyntheses in maxillofacial traumatology  and orthSince significant differences in biocompatibility and degradation profiles as well as in mechanical properties are observed between copolymeric biodegradable osteosynthesis systems, future clinical research should focus on a specific biodegradable system that has proven to be biocompatible in the long-term as well as having the most favorable mechanical properties for specific surgical indications. In addition, there is currently no evidence to support or refute the use of biodegradable osteosynthesis in load-bearing fracture fixation. Since current evidence suggests that load-sharing fixation of fractures using biodegradable osteosynthesis is feasible, the next step would be to focus on load-bearing biodegradable osteosynthesis of fractures. Finally, systematic reviews should include tools to assess the degree of clinical heterogeneity , and shoCurrent pre-clinical and clinical evidence indicates that biodegradable copolymeric osteosynthesis is a viable alternative to titanium osteosynthesis for fixation of both fractures and osteotomies, with similar efficacy ,184. FixAlthough copolymeric biodegradable and titanium osteosyntheses of osteotomies result in similar efficacy, both groups also have similar symptomatic osteosyntheses removal rates. Therefore, the primary advantage of biodegradable osteosyntheses in this population is neglected. Titanium systems are, therefore, still preferred due to lower risk of perioperative screw breakage, lower operation time, and better perioperative handling compared to biodegradable systems ,171,184.There is currently no evidence to support or refute the use of biodegradable osteosynthesis in load-bearing fracture fixation  or osteosyntheses in reconstructive surgery  . HoweverIn Both in maxillofacial trauma treatment and orthognathic surgery, the risk of perioperative screw breakage and perioperative time is significantly higher in the biodegradable compared to titanium osteosyntheses group ,184. PerScrew breakage is more likely when the difference between the torque applied to the screws for adequate fixation  and the maximum allowed torque  is small ,240. TheAn alternative to biodegradable screws is biodegradable pins that are inserted via ultrasonic welding , thereby diminishing the risk of perioperative screw breakage . This alBesides the advantages in perioperative handling, systems with ultrasound pin welding have significantly better mechanical properties compared to an identical system with conventional screws ,176. A pImprovements in mechanical properties may also result in smaller biodegradable osteosynthesis devices, thereby reducing issues regarding palpability of the system by patients, and stress-free closure of the incision by OMF-surgeons. In addition, low implant volume reduces the amount of acidic degradation products and thus reduces the risk of (late) foreign body reactions . StudiesBesides ultrasound welding, patient-specific osteosynthesis systems will also contribute to osteosynthesis systems with superior mechanical properties while reducing the total volume of the system, i.e., the system can be strengthened where necessary while removing excess material ,242,243.Other novel developments such as different types of coatings to prevent bacterial adhesion, surface topography adjustments to eliminate surrounding bacteria without the need for antibiotics, and coatings with antibiotics that can be released locally using ultrasound are promising developments to reduce infection risk . These lIn Titanium osteosynthesis systems have been improved to overcome the associated disadvantages. The titanium alloy production process can be altered in such a way to increase or decrease the elastic modulus of the titanium osteosynthesis plates ,24. By i2) to gain specific properties including inhibiting various bacteria from adhering  and reducing metal ion release from the implant ,24618,24Research should also aim to assess the least required mechanical properties for an osteosynthesis system for specific cases . Ideally, these insights should be incorporated into a validated model in which osteotomy and fracture parameters  can be easily adjusted. In addition, three-dimensional printing technologies such as stereolithography and selective laser sintering  means thIn this review, the current literature that compared the in vitro and in vivo performances  of different biodegradable and titanium osteosynthesis systems was discussed. It was shown that, based on current pre-clinical and clinical evidence, biodegradable copolymeric osteosyntheses are a viable alternative to titanium osteosyntheses when applied to treat maxillofacial trauma, with similar efficacy and significantly lower symptomatic osteosynthesis removal, but with higher perioperative screw breakage. For orthognathic surgery, biodegradable copolymeric osteosynthesis is also a valid alternative to titanium osteosyntheses, but with longer operation times compared to titanium osteosyntheses. Furthermore, it was shown that an osteosynthesis system composed of an amorphous copolymer , preferably using ultrasound welding with a well-contoured shape without acute angles, and that has sufficient mechanical properties  has the greatest potential as a biocompatible biodegradable copolymeric osteosynthesis system. Future research should focus on surface modifications  of titanium and biodegradable osteosynthesis systems to improve surgical handling, osteogenesis, and wear resistance. Finally, novel biodegradable materials  are promising candidates for the development of next-generation biodegradable osteosynthesis systems.


Several therapeutic agents for neurological disorders are usually not delivered to the brain owing to the presence of the blood–brain barrier (BBB), a special structure present in the central nervous system (CNS). Focused ultrasound (FUS) combined with microbubbles can reversibly and temporarily open the BBB, enabling the application of various therapeutic agents in patients with neurological disorders. In the past 20 years, many preclinical studies on drug delivery through FUS-mediated BBB opening have been conducted, and the use of this method in clinical applications has recently gained popularity. As the clinical application of FUS-mediated BBB opening expands, it is crucial to understand the molecular and cellular effects of FUS-induced microenvironmental changes in the brain so that the efficacy of treatment can be ensured, and new treatment strategies established. This review describes the latest research trends in FUS-mediated BBB opening, including the biological effects and applications in representative neurological disorders, and suggests future directions. Neurological disorders are medically defined as diseases that affect the brain and the nerves throughout the central and peripheral nervous systems. There are more than 600 neurological disorders, including degenerative diseases, such as Alzheimer’s or Parkinson’s; brain tumors; brain or spinal cord injury; convulsive disorders, such as epilepsy; and diseases of the blood vessels that supply the brain, such as stroke. However, the etiology of many central nervous system diseases has not yet been identified, and various new drugs are being developed accordingly. However, unlike other organs, the brain that oversees the central nervous system (CNS) is protected by a blood–brain barrier (BBB). The BBB separates the lumen of cerebral blood vessels from the brain parenchyma and selectively restricts permeation through tight junctions between vascular endothelial cells. Each of these tight junctions is composed of a protein complex of various transmembrane proteins, such as junctional adhesion molecules (JAM), occludin and claudin . OutsideMeanwhile, dysfunction of the BBB is a critical factor in various diseases such as epilepsy and stroke . ReporteSeveral pathways can cross the BBB to maintain brain homeostasis. Representative pathways include paracellular, transcellular, carrier-mediated, receptor-mediated, adsorptive-mediated, and cell-mediated pathways  Figure . To dateAn invasive surgical method, in which the skin is incised and the skull is opened to, has been used for a long time to treat brain diseases. However, minimally invasive or non-invasive surgical methods are being developed to avoid various risks associated with operating on a larger target area, such as functional damage to the brain and infection. Focused ultrasound (FUS) enables a superior penetration depth and spatial specificity without invasive surgical procedures or genetic modifications. Low-intensity FUS with microbubbles (MB) is a non-invasive technique that reversibly and temporarily opens the BBB ,15. SincThe incidence of Alzheimer’s disease (AD), the most representative neurodegenerative brain disease, is steadily increasing as the aging population increases. However, only drugs that can alleviate and delay symptoms are currently being used, and no specific treatment methods or therapeutic agents  have beeThe first preclinical study on FUS for AD aimed to deliver anti-Aβ antibodies targeting amyloid plaques into the brain by a BBB opening. Consequently, anti-Aβ antibodies bound to the Aβ plaques and rapidly reduced the plaque pathology . SubsequIn conclusion, combined treatment with FUS and Aducanumab reduced amyloid plaque levels, increased hippocampal neurogenesis, and restored cognitive function. Here, FUS activated phagocytic microglia and increased the number of astrocytes associated with amyloid plaques. This suggests that FUS can induce a reduction in amyloid plaques through phagocytosis. In addition, an RNA sequencing analysis showed that the combined treatment with FUS and Aducanumab upregulated neuroinflammation signaling, phagosome formation, reelin signaling, and CREB signaling . The immParkinson’s disease (PD) is a neurodegenerative brain disease accompanied by motor dysfunction due to the loss of dopaminergic neurons. PD is neuropathologically characterized by proteinaceous inclusions called Lewy bodies . NotablySince neurturin has been found to have neuroprotective and neuro-regenerative effects on dopaminergic neurons , the FUSGlioblastoma is the most aggressive brain tumor with a high recurrence rate and poor prognosis despite treatments such as resection, radiotherapy, and chemotherapy . The bloBrain metastasis represents an important predictor of mortality for various non-brain cancers such as breast cancer. Like primary brain tumors, brain metastases do not have an intact BBB, but most therapeutics still have lower intra-tumoral bioavailability than non-brain tumors . FUS stuWhether it is a primary brain tumor or a metastatic brain tumor, the critical factor in the tumor microenvironment is to what extent the anticancer drugs could be delivered into the target region. It has been reported that the delivery of chemotherapeutic agents with small molecular weights to the brain tumor microenvironment is approximately 3.9-fold higher under FUS-mediated BBB opening conditions . This enHowever, efflux transporters such as Pgp are overexpressed in cancer cells and prevent the uptake of anticancer drugs into the cells, resulting in resistance to them. FUS-mediated BBB opening temporarily inhibits Pgp expression, thereby preventing drug efflux and interfering with functional components of the BBB . AdditioIn 2014, Scarcelli et al. first reported that FUS-meditated BBB opening significantly increased the number of proliferating cells and newborn neurons in the dentate gyrus of the hippocampus . Since tIn addition, studies have recently reported that the regulation of ERK signaling cascades is involved in neurogenesis after BBB opening. However, it is necessary to understand the specific mechanism underlying FUS-induced neurogenesis. FUS can be a non-pharmacological therapeutic strategy for treating neurodegenerative brain diseases in older patients or patients with AD who have decreased hippocampal neurogenesis ,105.The glymphatic system is a unique fluid transport system of perivascular channels formed by astroglial cells to facilitate the efficient clearance of soluble proteins and metabolites from the CNS . Damage FUS-mediated BBB opening without any drug delivery in the AD model reduced the amyloid pathology, improved cognitive function, and increased the phagocytosis of glial cells ,34,50. SIt is not confirmed whether the glymphatic system studied in rodents also exists in humans . This isOne of the secondary effects beginning within hours after FUS-mediated BBB opening is inflammatory responses. Inflammatory responses are biological responses to harmful stimuli and act as a defense mechanism involving immune cells, blood vessels, and inflammatory mediators. Microglia are one of the basic innate immune cells in the brain. Studies have reported that microglia activation occurs 1, 6, and 24 h after FUS-mediated BBB opening ,121. FurRecently, research on various changes after FUS-mediated BBB opening has been explored using sequencing techniques such as transcriptomics and proteomics ,123,124.Since immune responses by FUS-mediated BBB opening depend on various factors, including differences in parameters and cavitation dose, inflammatory responses occur at different time points that can be prolonged or quickly vanish. As clinical studies on FUS-mediated BBB opening are actively expanding, we need to better understand varying inflammatory responses affected by FUS.This review briefly summarizes how FUS-mediated BBB opening is currently being studied in AD, brain tumors, and PD. Moreover, the neurogenesis or immune response induced when the BBB is opened and the glymphatic system associated with recent clearance were briefly introduced. Although not mentioned in this review, FUS studies are underway in various diseases, such as amyotrophic lateral sclerosis, traumatic brain injury, and stroke. They will be expanded to more diseases in the future.Currently, FUS is considered an innovative treatment method that effectively treats various neurological disorders that have been challenging to overcome for a long time. The effects and safety of FUS-mediated BBB opening on the brain have already been studied extensively. However, despite many technological advances in FUS over the past 20 years, research on the clinical applications of FUS-mediated BBB opening is only just beginning. Recently, clinical trials of FUS-mediated BBB opening have confirmed its safety in patients with AD ,129, PD Among the latest medical technologies being developed for the treatment of many neurological disorders, one of the major directions is a noninvasive or minimally invasive treatment. The main advantage of FUS is that it is a non-invasive technology; therefore, it is relatively safe and can be used repeatedly. FUS may be established as a representative treatment technique for neurological disorders in the near future.


A central problem in clinical neuroscience is that the regenerative capacity of the injured adult mammalian central nervous system (CNS) is extremely limited, which usually leads to permanent neurological deficits. The reason there is no regeneration in the CNS after the injury is because the injury does not increase the intrinsic growth capacity of the injured neurons, their growth state remains unchanged or even suppressed and they continue to respond to inhibitory cues in the CNS , exchange protein directly activated by cAMP (Epac), and cyclic nucleotide-gated channel. Epac is expressed as two isoforms, Epac1 and Epac2, which exhibit a different expression pattern in vertebrates. Epac1 expressed in early neurons contributes to primary axon development, and Epac2 expressed in mature neurons modulates the dendrite stability and outgrowth. cAMP is also responsible for axonal guidance as low cAMP concentrations in the growth cone result in repulsion in the presence of guidance cues such as MAG and Netrin-1, but high concentrations result in attraction. Given the multi roles of cAMP in the CNS, cAMP is a potential candidate for CNS regeneration impairments.Adult neurons in the peripheral nervous system (PNS) can be switched or transformed, however, into an actively growing state. For dorsal root ganglion (DRG) sensory neurons, preconditioning the sensory neurons by applying peripheral nerve injury both increases axonal growth and partially overcomes myelin inhibition, acquiring the novel capacity to regenerate in the CNS  into the neurons and outgrowth of neurites that are extending into astrocytic scars in SCI rats. Both BMSC-extracellular vesicles and let-7a-5p promoted the differentiation of neural stem cells into neurons and the inhibition of let-7a-5p attenuate the BMSC extracellular vesicle-induced effects through activation of TGF-beta/Smad signaling pathway.Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising treatments for SCI. In the review by Fuchs et al. present how plasma membrane proteins phospholipid phosphatase-related proteins (PLPPRs) functions in filopodia formation, axon guidance and branching during nervous system development and regeneration, as well as in the control of dendritic spine number and excitability. PLPPRs govern neurite and/or branch formation in a PIP3-dependent manner and axon guidance is regulated though interaction with TRIM9 and TRIM67, which are E3 ubiquitin ligases that localize to filopodia tips and function in axon projection. Although the interaction of PLPPR with LPA signaling is yet to be elucidated, PLPPR remains an intriguing target in CNS regeneration.Neuronal plasma membrane proteins orchestrate neuronal differentiation, growth and plasticity in the developing and adult nervous system and the review by Zhang et al., shows that lampreys can regenerate their axons after SCI increase CSPGs expression. Lecticans are the major component of CSPG family and four types of lamprey lecticans  were found in glia and neurons. Of these lecticans, upregulation of lectican D was particularly strong and persistent, at least to 10 weeks post-SCI, when many axons are already regenerating into the scar, suggesting that post-SCI, some CSPGs, particularly lectican D, might actually promote axon growth or guidance and this may change the view for overcoming inhibitory environment.Among Nogo, MAG, and oMGP, chondroitin sulfate proteoglycans (CSPGs) are believed to be the major inhibitory cues in the CNS. Interestingly, review by Avraham et al. discovered that combination of overexpressed transcription factors Ctcf and Yy1 significantly enhances axonal growth by over 50% but interestingly, does not show significant growth when overexpressed independently. For traumatic peripheral nerve injuries, the tools we have for nerve repair is limited to direct nerve suture, autologous or artificial nerve graft for nerve defects and nerve transfers. However, the procedures are limited by the donor nerves, so as a surgeon, we truly hope for this advancement made in basic science to be transitioned to clinical practice. For patients with limited function, small improvement can bring huge changes.Despite the regenerative capability of PNS neurons, this capacity is still not enough to restore meaningful function after peripheral nerve injury, depending on the site, magnitude, and the type of injury. In order to achieve meaningful function after peripheral nerve injury, the regenerating axons must reach their target muscle before the distal Schwann cells and the muscles degenerate. There are three strategies to promote PNS regeneration. (1) Acceleration of neuronal intrinsic growth, (2) prevention of Schwann cell degeneration apoptosis, and (3) prevention of muscle irreversible degeneration. Using RNA sequencing at different time points in cultured dorsal root ganglia neurons. The author confirms being the sole contributor of this work and has approved it for publication.